Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes
Open accessAbstract
Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.
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TL;DR
This review argues that Alzheimer's disease is best explained by a multifactorial hypothesis rather than any single-mechanism model, and that plant-derived polyphenols and monoterpenes are promising multi-target agents against Aβ aggregation, neuroinflammation, oxidative stress, and brain insulin resistance. It catalogs mechanistic and preclinical evidence for specific compounds while noting that clinical translation remains limited by poor pharmacokinetics and trial design.
Key findings
- The review frames AD as multifactorial, with Aβ aggregation, Tau hyperphosphorylation, oxidative stress/mitochondrial dysfunction, neuroinflammation, and brain insulin resistance converging; it states AD affects over 40 million people worldwide and accounts for up to 70% of dementia cases.
- Polyphenols reviewed (resveratrol, quercetin, luteolin, EGCG, curcumin, genistein) are reported to inhibit Aβ aggregation, modulate neuroinflammation (e.g., NF-κB, p38 MAPK, iNOS/COX-2), scavenge ROS, and improve insulin sensitivity; resveratrol in a clinical trial decreased CSF Aβ levels and neuroinflammation biomarkers, though a pilot study showed improved psychomotor speed without significant memory benefit.
- Monoterpenes reviewed (geniposide, catalpol, linalool, limonene) show antioxidant, anti-inflammatory, anti-AChE, and anti-diabetic activities; limonene's anti-AChE activity is reported as almost comparable to galantamine.
- The paper states that despite extensive preclinical promise, clinical results for natural compounds have been "mostly insufficient or disappointing," attributing this to poor BBB penetration, rapid metabolism, dosing extrapolation difficulties, and trial design issues.
Methods
This is a narrative review; no primary data, systematic search strategy, or meta-analysis is reported. It synthesizes mechanistic, in vitro, in vivo, and clinical literature on AD pathogenesis and on polyphenol and monoterpene bioactivities, organized by compound class and pathogenic mechanism.
Limitations
The paper itself acknowledges that preclinical literature may overestimate benefits of natural compounds, that dose extrapolation from cells/animals to humans is difficult, that gut microbiota and dietary intake complicate polyphenol evaluation, and that clinical trial participant selection is challenging. Evident from the text: no systematic search or inclusion criteria are described, so compound selection appears illustrative rather than exhaustive; many cited findings are from animal or cell models, and the review reports no quantitative synthesis.
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Claims the paper makes
0 of 337 cited sources checked · 0 supported · 0 flagged
- Findingcitation
A study from our group shows that limonene counteracts the reduction of mitochondrial dehydrogenase activity, increase of intracellular ROS levels, and nuclear morphology alterations induced by Aβ1-42 oligomers in primary cortical neurons.
“Very recently, a study from our group has shown that limonene is able to counteract the reduction of mitochondrial dehydrogenase activity, increase of intracellular ROS levels and nuclear morphology alterations induced by Aβ1-42 oligomers in primary cortical neurons (Piccialli et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piccialli et al., 2021 source
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- Findingcitation
Our results confirm that limonene exerts anti-AChE activity almost comparable to that of galantamine.
“Moreover, our results also confirmed that limonene is able to exert an anti-AchE activity almost comparable to that of galantamine (Piccialli et al., 2021), thus highlighting its multi-target therapeutic potential.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piccialli et al., 2021 source
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- Findingcitation
The antioxidant activity of limonene is crucial in preventing the increase of outward transient potassium currents, which play a critical role in triggering caspase activation and apoptotic cell death.
“In the same study, the antioxidant activity of limonene has been crucial in preventing the increase of outward transient potassium currents, which were shown to play a critical role in triggering caspase activation and apoptotic cell death (Pannaccione et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pannaccione et al., 2007 source
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- Premisecitation
Tau pathology can cause neurodegeneration and neuroinflammation regardless of Aβ pathology.
“Moreover, it has been shown that the Tau pathology could cause neurodegeneration and neuroinflammation regardless of the Aβ pathology (Kametani and Hasegawa, 2018; Laurent et al., 2018).”
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- cites Laurent et al., 2018 source
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- Premisereasoning
The cleavage site for α-secretase lies within the Aβ sequence of APP and hence precludes Aβ formation.
“Importantly, the cleavage site for the α-secretase lies within the Aβ sequence of the APP and hence precludes the Aβ formation.”
Quote in the paperNot a substantial claim
- Interpretationreasoning
The common limitation of the proposed Alzheimer's disease hypotheses is that they overemphasize a single specific mechanism, underestimating other mechanisms.
“However, the common limitation of these hypotheses is that, similarly to the “amyloid cascade hypothesis,” they overemphasize a single specific mechanism, underestimating other mechanisms.”
Quote in the paperSubstantial claim - Premisenone given
In the amyloidogenic pathway, APP is processed first by β-secretase (BACE-1) and then by γ-secretase, generating monomeric Aβ fragments.
“In the so-called “amyloidogenic pathway” the APP is instead processed first by the β-secretase, also known as β-site APP Cleaving Enzyme 1 (BACE-1), and then by the γ-secretase, which generates monomeric Aβ fragments.”
Quote in the paperSubstantial claim - Interpretationreasoning
Alzheimer's disease neurodegeneration is the result of different pathogenic mechanisms and their interplay, rather than a single deleterious process.
“considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay.”
Quote in the paperSubstantial claim - Premisenone given
The Aβ peptide, consisting of 39-43 amino acid residues, is produced in the brain upon cleavage of APP by proteolytic enzymes.
“The Aβ peptide, consisting of 39–43 amino acid residues, is produced in the brain upon the cleavage of the APP by proteolitic enzymes.”
Quote in the paperNot a substantial claim - Premisecitation
Total Aβ burden depends on the balance between production and clearance or degradation rates.
“The total Aβ burden depends on the balance between production and clearance or degradation rates (Hardy, 1997; George-Hyslop and Rossor, 2001).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hardy, 1997 source
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- cites George-Hyslop and Rossor, 2001
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- Premisecitation
Extracellular deposits of Aβ aggregates (neuritic plaques) are the primary hallmarks found in the brain of patients diagnosed with Alzheimer's disease.
“The extracellular deposits of Aβ aggregates, namely the neuritic plaques, are the primary hallmarks found in the brain of the patients diagnosed with AD (Selkoe and Hardy, 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Selkoe and Hardy, 2016 source
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- Premisecitation
Aβ aggregation and accumulation start at the cellular level many years before the clinical diagnosis of Alzheimer's disease.
“However, the Aβ aggregation and accumulation start at the cellular level many years before the clinical diagnosis of AD (Morris et al., 1996; Brannstrom et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
A therapeutic strategy targeting simultaneously different pathways considered as determinants of Alzheimer's disease pathogenesis seems to be the most promising approach to modify disease progression.
“In this view, a therapeutic strategy targeting simultaneously different pathways considered as determinants of the AD pathogenesis seems to be the most promising approach to modify the disease progression.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Multiple etiological factors may converge in a common pathological manifestation in Alzheimer's disease.
- Interpretationreasoning
The multifactorial hypothesis seems to be the most convincing model able to explain why all drugs developed under the one-molecule, one-target paradigm have displayed poor therapeutic potential.
“This seems to be the most convincing model able to explain why all the drugs developed under the “one-molecule, one-target” paradigm have displayed poor therapeutic potential.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Multiple etiological factors may converge in a common pathological manifestation in Alzheimer's disease.
- Premisecitation
Aβ clearance may occur through transport into cerebrospinal fluid, blood across the blood-brain barrier, and removal by brain-resident macrophages.
“The Aβ clearance may occur through the transport into the cerebrospinal fluid, the blood across the blood-brain barrier (BBB), and the removal by brain-resident macrophages (Yoon and Jo, 2012).”
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- Premisecitation
According to the cellular phase, dysfunction of the neuro-glial-vascular unit along with impairment of astrocytic and microglial homeostatic functions mainly contribute to precipitate Alzheimer's disease in a clinical disease.
“According to the so-called “cellular phase,” an extension of the amyloid cascade hypothesis proposed by De Strooper and Karran (De Strooper and Karran, 2016), the dysfunction of the neuro-glial-vascular unit along with the impairment of astrocytic and microglial homeostatic functions mainly contribute to precipitate AD in a clinical disease.”
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- Premisereasoning
Astrocytes and microglia are involved in tight regulation of Aβ clearance and degradation.
“Glial cells seem to play a key role in this process, since both astrocytes, the predominant form of glial cells in the central nervous system (CNS), and microglia, the major phagocytic cells in the brain, are involved in the tight regulation of Aβ clearance and degradation.”
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Oxidative stress, mitochondrial dysfunction, astrocytic and microglial activation, membrane perturbation, and loss of ionic homeostasis are downstream events of Aβ1-42 aggregation and accumulation.
“Oxidative stress, mitochondrial dysfunction, astrocytic and microglial activation, membrane perturbation, and loss of ionic homeostasis are, at the cellular level, some of the events downstream the Aβ1-42 aggregation and accumulation (Selkoe and Hardy, 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Selkoe and Hardy, 2016 source
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- Premisecitation
The capability of astrocytes and microglia to internalize and degrade Aβ is strictly correlated with their aberrant activation during Alzheimer's disease progression.
“Importantly, the capability of astrocytes and microglia to internalize and degrade Aβ (Guénette, 2003; Hansen et al., 2018) is strictly correlated with their aberrant activation during the AD progression (Bates et al., 2009; Ries and Sastre, 2016).”
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Tau can spread throughout the brain by moving from one cell to another anatomically connected cell, exemplifying prion-like propagation.
“Another noteworthy feature of Tau is its ability to spread throughout the brain by moving from 1 cell to another, anatomically connected, cell hence perfectly exemplifying the prion-like propagation characteristic of several proteinopathies (Dujardin and Hyman, 2019).”
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- Premisecitation
Aggregation of Aβ1-42 monomers first gives rise to soluble oligomeric species, which further assemble to form insoluble fibrils accumulating in brain parenchyma and other tissues.
“The aggregation of Aβ1-42 monomers first gives rise to soluble oligomeric species, which further assemble to form insoluble aggregates known as fibrils accumulating in the brain parenchyma and other tissues (Chen et al., 2017).”
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- Premisecitation
Aβ exerts oxidative stress in astrocytes by altering astrocytic Ca2+ homeostasis and mitochondrial function.
“Moreover, Aβ has been recognized to exert oxidative stress in astrocytes by altering astrocytic Ca2+ homeostasis and mitochondrial function (Abramov et al., 2004; Verkhratsky et al., 2017; Piccialli et al., 2020).”
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Different kinases are involved in Tau phosphorylation, including GSK-3β, protein kinase A, p38 MAPK, Erk1/2, and JNK1/3.
“Different kinases have been demonstrated to be involved in Tau phosphorylation, including the glycogen synthase kinase 3β (GSK-3β), protein kinase A, p38 mitogen activated protein kinase (MAPK), extracellular signal-related kinases (Erk1/2), and c-Jun N-terminal kinases (JNK) 1/3 (Martin et al., 2013).”
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- Interpretationcitation
Aβ-induced dysregulation of ionic homeostasis in astroglial cells may crucially contribute to their pathological remodelling.
“In turn, the Aβ-induced dysregulation of ionic homeostasis in astroglial cells may crucially contribute to their pathological remodelling (Boscia et al., 2017; Verkhratsky et al., 2017; Piccialli et al., 2020).”
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Severe mitochondrial dysfunction in the brain of Alzheimer's disease patients has been extensively demonstrated.
“The occurrence of a severe mitochondrial dysfunction in the brain of AD patients has been extensively demonstrated (Abate et al., 2020).”
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- Premisenone given
Aβ aggregates may induce Tau hyperphosphorylation by enhancing the activity of several kinases including GSK-3β and MAPKs.
“It is known that Aβ aggregates may induce Tau hyperphosphorylation by enhancing the activity of several kinases including GSK-3β and MAPKs.”
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Aβ degradation is ensured by proteases such as cathepsin and insulin-degrading enzyme (IDE), which cleave Aβ into smaller soluble fragments.
“The Aβ degradation is ensured by some proteases, such as cathepsin and the insulin-degrading enzyme (IDE), which cleave the Aβ into smaller soluble fragments (Miners et al., 2011; Kurochkin et al., 2018).”
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Oxidative stress and mitochondrial dysfunction are prominent features of many neurodegenerative diseases including Alzheimer's disease.
“Oxidative stress and mitochondrial dysfunction are prominent features of many neurodegenerative diseases including AD (Butterfield, 2002; Butterfield and Boyd-Kimball, 2018; Sharma and Kim, 2021).”
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Multiple lines of evidence suggest that hyperphosphorylation and aggregation of Tau may be a major trigger of Alzheimer's disease neurodegeneration.
“Multiple lines of evidence suggest that the hyperphosphorylation and aggregation of the protein Tau may be a major trigger of AD neurodegeneration.”
Quote in the paperSubstantial claim - Premisenone given
In Alzheimer's disease, an imbalance between kinase and phosphatase activities causes Tau hyperphosphorylation.
“In AD, an imbalance between kinase and phosphatase activities causes Tau hyperphosphorylation.”
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Aggregated Tau forms β-sheet-containing amyloid fibrils, known as paired helical filaments.
“Similarly to Aβ, aggregated Tau forms β-sheet-containing amyloid fibrils, known as paired helical filaments (Mandelkow et al., 2007).”
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- Premisecitation
Cerebral amyloid angiopathy exacerbates Alzheimer's disease pathology.
“Unsurprisingly, such a condition, known as cerebral amyloid angiopathy exacerbates the AD pathology (Shabir et al., 2018).”
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- Premisenone given
Tau toxicity is considered a major driver of Alzheimer's disease neurodegenerative cascade.
“Although Tau toxicity is considered a major driver of AD neurodegenerative cascade, there is still a significant gap in the knowledge of the molecular mechanimsms underlying tau-mediated neuroinflammation.”
Quote in the paperSubstantial claim - Premisecitation
Many components of the antioxidant system are particularly affected during Alzheimer's disease progression.
“Alongside, many components of the antioxidant system have been shown to be particularly affected during the AD progression.”
Quote in the paperSubstantial claim - Premisecitation
Aβ-induced oxidative stress leads to activation of p38 MAPK and subsequent tau hyperphosphorylation.
“Importantly, it has been reported that the Aβ-induced oxidative stress leads to the activation of p38 MAPK and subsequent tau hyperphosphorylation (Giraldo et al., 2014).”
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- Premisecitation
Blood-brain barrier disruption and increased permeability occur in the early phase of Alzheimer's disease pathology.
“Indeed, the BBB disruption and increased permeability have been shown to occur in the early phase of the AD pathology (van de Haar et al., 2016).”
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- Premisecitation
Neuroinflammation and subsequent impairment of the neuro-glial-vascular unit occur before disruption of Aβ homeostasis.
“On the other hand, it has been reported that neuroinflammation and the subsequent impairment of the neuro-glial-vascular unit, which is mainly composed of neuronal, glial, and vascular cells supporting the BBB (Harder et al., 2002), occur before the disruption of the Aβ homeostasis (Zlokovic, 2011).”
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Both insulin and insulin-like growth factor 1 can influence brain energy homeostasis, neuronal survival, and learning and memory processes.
“Accordingly, it is now clear that both insulin and its analogue, the insulin-like growth factor 1 (IGF-1), can influence brain energy homeostasis, neuronal survival, and learning and memory processes (Kapogiannis and Mattson, 2011).”
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- Premisenone given
Microglia stimulate formation of nitric oxide by inducible nitric oxide synthase.
“In particular, microglia stimulate the formation of NO by the inducible NO synthase (iNOS).”
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NF-κB plays a crucial role in neuroinflammation as master regulator of transcription of pro-inflammatory genes.
“NF-κB nuclear transcription factor plays a crucial role in neuroinflammation, as it is the master regulator of the transcription of pro-inflammatory genes.”
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Many experimental data suggest that oxidative stress and mitochondrial dysfunction induce an increase in the amyloidogenic cleavage of APP and an aberrant Aβ production.
“On the other hand, many experimental data suggest that oxidative stress and mitochondrial dysfunction induce an increase in the amyloidogenic cleavage of the APP and an aberrant Aβ production (Misonou et al., 2000; Perez Ortiz and Swerdlow, 2019).”
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- cites Perez Ortiz and Swerdlow, 2019
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Neuroinflammation is a well-documented downstream event of Aβ accumulation.
“Furthermore, neuroinflammation is a well-documented downstream event of the Aβ accumulation (Akiyama et al., 2000).”
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Decreased levels of Nrf2, a transcription factor negatively regulated by NF-κB and involved in antioxidant response mechanisms, have been reported in brains of Alzheimer's disease patients.
“In addition, decreased levels of Nrf2, a transcription factor negatively regulated by NF-κB (Liu et al., 2008) that is involved in antioxidants response mechanisms (Nair et al., 2008), have been reported in the brains of AD patients (Ramsey et al., 2007).”
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Nitric oxide triggers neurodegenerative processes by reducing ATP synthesis through blocking neuronal mitochondrial respiration at cytochrome C oxidase level, inducing ROS production.
“NO, in turn, triggers neurodegenerative processes since it reduces the ATP synthesis by blocking the neuronal mitochondrial respiration at the cytochrome C oxidase level, hence inducing the production of ROS.”
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p38 MAPK, activated by ROS produced upon microglial activation, activates NF-κB.
“The p38 MAPK, which is activated by the ROS produced upon microglial activation, was shown to activate NF-κB (Kheiri et al., 2018).”
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- Premisecitation
Impairment of brain glucose/energy metabolism induced by metabolic disorders such as obesity, diabetes, and hyperinsulinemia is widely accepted to be implicated in Alzheimer's disease progression.
“Among those attracting particular attention, the impairment of brain glucose/energy metabolism induced by metabolic disorders such as obesity, diabetes and hyperinsulinemia, has been widely accepted to be implicated in the AD progression (de la Monte, 2017; Ettcheto et al., 2020).”
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NF-κB has been proposed as a molecular factor underlying some sporadic forms of Alzheimer's disease.
“Moreover, it has also been proposed as a molecular factor underlying some sporadic forms of AD (Chen et al., 2012).”
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The increase of these inflammatory markers seems to be correlated with the cognitive impairment occurring in Alzheimer's disease.
“Importantly, the increase of these markers seems to be correlated with the cognitive impairment occurring in AD (Solfrizzi et al., 2006; Westin et al., 2012).”
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The Aβ peptide is oxidative per se because of the peculiar chemical/electrostatic features of its secondary structure.
“First, the Aβ peptide is oxidative per se because of the peculiar chemical/electrostatic features of its secondary structure.”
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Soluble Aβ oligomers can activate microglia and production of pro-inflammatory cytokines.
“Importantly, it has been demonstrated that soluble Aβ oligomers can activate microglia and the production of pro-inflammatory cytokines (Selkoe and Hardy, 2016; Yang et al., 2017).”
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Nrf2 deficiency increases levels of pro-inflammatory mediators.
“Based on the evidence that an Nrf2 deficiency increases the levels of pro-inflammatory mediators, there is a growing interest in finding any Nrf2 pharmacological activators.”
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A sustained inflammatory state in the brain is a major contributor in Alzheimer's disease pathogenesis.
“A growing amount of evidence has revealed that a sustained inflammatory state in the brain is a major contributor in the AD pathogenesis (Dhapola et al., 2021).”
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- Premisecitation
Both in vitro and in vivo studies pointed out the Aβ peptide as a target molecule of metal-catalyzed oxidation.
“Moreover, both in vitro and in vivo studies pointed out the Aβ peptide as a target molecule of metal-catalyzed oxidation (Näslund et al., 1994; Kowalik-Jankowska et al., 2004; Inoue et al., 2009).”
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Aβ oligomers may induce ROS production through several mechanisms.
“Undoubtedly, Aβ oligomers may induce ROS production through several mechanisms.”
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Activated microglial cells can exert both neurotoxic and neuroprotective effects depending on the phenotype they acquire upon activation.
“The role of activated microglial cells is crucial in neuroinflammation since they can exert both neurotoxic and neuroprotective effects depending on the phenotype they acquire upon activation (Woodburn et al., 2021).”
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- Premisereasoning
Aβ insertion into the lipid bilayer of the neuronal plasma membrane induces lipid peroxidation in a direct manner.
“For the same reason, the Aβ insertion into the lipid bilayer of the neuronal plasma membrane induces lipid peroxidation in a direct manner (Butterfield, 2002).”
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- Premisecitation
Phenolic compounds interfere with Aβ peptide aggregation by targeting one or multiple steps.
“A huge number of phenolic compounds have displayed the capability to interfere with the aggregation of the Aβ peptide by targeting one or multiple steps (Ma et al., 2020; Stefanescu et al., 2020)”
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- cites Stefanescu et al., 2020 source
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Tau hyperphosphorylation is a primary factor in AD independently of Aβ.
“many reports showed that Tau hyperphosphorylation is a primary factor in AD independently on Aβ”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bloom, 2014 source
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- Premisenone given
Insulin signaling crucially affects many aspects of mitochondrial metabolism, which plays a central role in controlling cellular metabolism and nutrient sensing.
“However, insulin signaling crucially affects many aspects of mitochondrial metabolism, which in turn plays a central role in controlling cellular metabolism and nutrient sensing.”
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γ-secretase inhibitors failed clinical trials because of many side effects.
“γ-secretase inhibitors failed clinical trials because of many side effects (Miranda et al., 2021)”
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Comorbidities including obesity, diabetes, cardiovascular diseases, stroke, and depression affect AD pathogenesis and progression.
“a broad range of comorbidities and the underlying biological mechanisms have been shown to affect the AD pathogenesis and progression, including obesity, diabetes, cardiovascular diseases, stroke, and depression (Santiago and Potashkin, 2021)”
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- Premisecitation
Amyloid plaques and neurofibrillary tangles may act in parallel or in combination to contribute to AD development.
“the formation of amyloid plaques and neurofibrillary tangles may in fact act in parallel or in combination to contribute to the development of AD (Bloom, 2014)”
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Epidemiological studies indicate that type 2 diabetes mellitus is associated with an increased risk to develop Alzheimer's disease compared to normal people.
“Importantly, epidemiological studies indicate that T2DM is associated to an increased risk to develop AD in comparison to normal people (Biessels et al., 2006).”
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Increased oxidative stress, mitochondrial dysfunction, neuroinflammation, and metabolic alterations may be critical in initiation of neurodegeneration in AD.
“increased levels of oxidative stress, mitochondrial dysfunction, neuroinflammation, and metabolic alterations, which are prominent features of aging, may all be critical in the initiation of the neurodegeneration occurring in AD (Song et al., 2021)”
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- The authors state this as an assumption: Aging constitutes a predominant risk factor for AD.
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The BACE-1 inhibitor Lanabecestat failed clinical trials due to lack of effectiveness.
“these trials proved unsuccessful due to the lack of effectiveness, as for the BACE-1 inhibitor Lanabecestat (Miranda et al., 2021)”
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Insulin resistance has been found in association with Alzheimer's disease independently of coincident type 2 diabetes mellitus.
“Insulin resistance has also been found in association with AD independently on coincident T2DM (Bosco et al., 2011).”
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Natural inhibitors interact directly with Aβ peptide through covalent or non-covalent bindings.
“These actions are underlain by the direct interaction of the compounds with the Aβ peptide through covalent or non-covalent bindings (Henriquez et al., 2020; Ma et al., 2020)”
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- cites Ma et al., 2020
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Despite being useful in improving quality of life, these drugs are not able to interrupt or delay Alzheimer's disease progression.
“However, despite useful in improving the quality of life of the patients, they are not able to interrupt or delay the AD progression.”
Quote in the paperSubstantial claim - Interpretationreasoning
The evidence of insulin resistance and reduced insulin signaling in Alzheimer's disease led to consider AD as a brain diabetes or a "Type 3 diabetes".
“This evidence led to consider AD as a brain diabetes or a “Type 3 diabetes”.”
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Many natural compounds act as multi-target agents with fewer side effects than synthetic counterparts.
“Many of them have also been demonstrated to act as multi-target agents with reported fewer side effects in comparison to their synthetic counterparts (Rahman et al., 2021)”
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Lifestyle interventions including physical exercise, caloric restriction, and antioxidant nutritional supplements are effective in reducing modifiable AD risk factors.
“life-style interventions including physical exercise, caloric restriction and nutritional supplements with antioxidant compounds are effective in reducing the modifiable AD risk factors”
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Insulin resistance leads to reduced Aβ degradation by insulin-degrading enzyme, promoting Aβ accumulation.
“It is also worth noting that insulin resistance leads to a reduced Aβ degradation by IDE, hence promoting the Aβ accumulation (Ho et al., 2004; Zhao et al., 2004; Petrov et al., 2015).”
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Umibecestat caused cognitive worsening in patients.
“or because of a cognitive worsening in the patients, as in the case of Umibecestat (Neumann et al., 2018)”
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Quercetin reduces iNOS-mediated NO production in LPS-treated BV2 microglial cells by suppressing NF-κB activation.
“Quercetin is also able to reduce iNOS-mediated NO production in lipopolysaccharide (LPS)-treated BV2 microglial cells by suppressing NF-κB activation (Kang et al., 2013)”
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- Premisecitation
Resveratrol affects Aβ production by inhibiting β-secretase activity.
“resveratrol has been demonstrated to affect the Aβ production by inhibiting the activity of β-secretase (Choi et al., 2011; Koukoulitsa et al., 2016)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Resveratrol ingestion stimulates glucose uptake by increasing translocation of GLUT4.
“resveratrol ingestion is able to stimulate glucose uptake by increasing the translocation of GLUT4 (Szkudelski and Szkudelska, 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Szkudelski and Szkudelska, 2011
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- Premisecitation
Natural compounds with strong antioxidant activity are a promising approach for AD treatment.
“Overwhelming evidence has also highlighted the use of natural compounds with a strong antioxidant activity as a promising approach for the AD treatment (Guan et al., 2021; Walia et al., 2021)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Quercetin attenuates IL-1β-mediated inflammation in astrocytes and neuronal cultures by inhibiting release of IL-6 and IL-8.
“quercetin has been demonstrated to attenuate the inflammation mediated by IL-1β in astrocytes and neuronal cultures by inhibiting the release of IL-6 and IL-8 (Sharma et al., 2007)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sharma et al., 2007 source
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- Premisenone given
Some natural products activate Nrf2, which underlies at least in part their anti-inflammatory activity.
“Other natural products are able to activate Nrf2, a mechanism that has been shown to underlie at least in part their anti-inflammatory activity.”
Quote in the paperNot a substantial claim - Premisecitation
Resveratrol inhibits microglial activation in APP/PS1 mice.
“to inhibit microglial activation in APP/PS1 mice (Capiralla et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Capiralla et al., 2012 source
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- Premisecitation
Phytochemicals including flavonoids, polyphenols, terpenoids, and carotenoids target multiple signaling pathways responsible for microglial activation and release of pro-inflammatory mediators, or NF-κB and p38 MAPK activation.
“Many phytochemicals including flavonoids and other polyphenols, terpenoids, and carotenoids have indeed the ability to target multiple signaling pathways responsible for microglial activation and the subsequent release of pro-inflammatory mediators, or those involved in the activation of NF-κB and p38 MAPK”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Resveratrol inhibits neuroinflammation.
“Resveratrol has been shown to exert an inhibitory activity on neuroinflammation in several studies (Candelario-Jalil et al., 2007; Lu et al., 2010; Potter et al., 2013; Zhang R et al., 2013; Wang et al., 2015)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Higher number of catechol moieties increases inhibitory activity of polyphenolic inhibitors.
“the higher the number of catechol moieties the more the inhibitory activity increases (Tsunoda et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tsunoda et al., 2018 source
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- Premisecitation
Anti-inflammatory and antioxidant properties contribute to therapeutic potential of natural compounds.
“the presence of anti-inflammatory and antioxidant properties is another crucial feature of natural compounds contributing to their therapeutic potential (Uddin et al., 2021)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Uddin et al., 2021 source
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- Premisecitation
A guaiacol moiety is required for anti-aggregating activity of polyphenolic inhibitors.
“a guaiacol moiety is required for the anti-aggregating activity of polyphenolic inhibitors (Tomaselli et al., 2019)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tomaselli et al., 2019 source
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- Premisecitation
Evidence of efficacy of natural antioxidant compounds has been limited possibly due to poor bioavailability or treatment timing.
“evidence of their efficacy has been quite limited thus far possibly due to a poor bioavailability or to the time point in which the treatment is undertaken (Forman and Zhang, 2021)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Forman and Zhang, 2021 source
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- Premisecitation
Resveratrol modulates Aβ clearance through several mechanisms.
“to modulate the Aβ clearance through several mechanisms (Zhang et al., 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2014 source
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- Premisecitation
Resveratrol inhibits production of NO, TNF-α and IL-1β in astrocytic and microglial cells.
“it has been shown to inhibit the production of pro-inflammatory factors such as NO, TNF-α and IL-1β in both astrocytic and microglial cells (Yao et al., 2015; Zhao et al., 2018)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisenone given
Flavonoids act directly as reactive oxygen scavengers by donating hydrogen.
“flavonoids are largely known for their antioxidant activity as they can act directly as reactive oxygen scavengers by donating hydrogen.”
Quote in the paperNot a substantial claim - Premisecitation
Nano-encapsulation of resveratrol in lipid carriers or liposomes or polymeric particles could ameliorate its pharmacodynamics and pharmacokinetics.
“the nano-incapsulation in lipid carriers or liposomes as well as the insertion into polymeric particles could ameliorate both pharmacodynamics and pharmacokinetics of resveratrol (Andrade et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Andrade et al., 2018 source
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- Premisecitation
Quercetin acts as scavenger of ROS and RNS.
“quercetin has been shown to act as a scavenger of both ROS and RNS (Boots et al., 2008)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Boots et al., 2008 source
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- Premisecitation
Resveratrol counteracts HFD-induced insulin resistance.
“resveratrol has been suggested to counteract the HFD-induced insulin resistance (Mendez-del Villar et al., 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mendez-del Villar et al., 2014 source
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- Premisecitation
Diet supplemented with luteolin ameliorates obesity and insulin resistance in mice.
“a diet supplemented with luteolin has been demonstrated to ameliorate obesity and insulin resistance in mice (Xu et al., 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xu et al., 2014
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- Premisecitation
In transgenic APPSWE Tg2576 mice, intraperitoneal EGCG for 2 months significantly reduces Aβ levels.
“In transgenic APPSWE Tg2576 mice, the intraperitoneal treatment with EGCG for 2 months is associated to a significant reduction of the Aβ levels”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rezai-Zadeh et al., 2005 source
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- Premisecitation
Luteolin improves insulin sensitivity in many cell types, including adipocytes and endothelial cells.
“luteolin has been shown to improve insulin sensitivity in many cell types, including adipocytes and endothelial cells (Ding et al., 2010; Deqiu et al., 2011)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
EGCG may disrupt Aβ protofibrils by forming π-π and hydrogen bonding interactions.
“ECGC may disrupt Aβ protofibrils by forming π-π and hydrogen bonding interactions (Zhan et al., 2020; Li M et al., 2021)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Zhan et al., 2020 source
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- cites Li M et al., 2021
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- Premisecitation
Luteolin improves cognitive abilities in a mouse model of vascular dementia by modulating pro-inflammatory and pro-apoptotic proteins and stimulating neurogenesis.
“luteolin has been demonstrated to improve cognitive abilities in a mouse model of vascular dementia by modulating the expression of pro-inflammatory and pro-apoptotic proteins and by stimulating neurogenesis (Siracusa et al., 2017; Cordaro et al., 2020)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
EGCG treatment ameliorates mitochondrial respiration deficits in children affected by Down syndrome.
“EGCG treatment ameliorates mitochondrial respiration deficits in children affected by Down syndrome (Scala et al., 2021)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Scala et al., 2021 source
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- Premisecitation
Dietary administration of luteolin reduces microglial activation in senescent mice.
“a dietary administration of luteolin reduces microglial activation in senescent mice (Burton et al., 2016)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Burton et al., 2016 source
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- Premisereasoning
Clinical results on EGCG efficacy in ameliorating cognitive functions have not reflected therapeutic potential from preclinical studies.
“clinical results on the efficacy of EGCG in ameliorating cognitive functions have not reflected the therapeutic potential emerged in pre-clinical studies.”
Quote in the paperNot a substantial claim - Premisecitation
Quercetin positively modulates Nrf2 signaling.
“to positively modulate Nrf2 signaling (Arredondo et al., 2010; Molaei et al., 2020; Yu et al., 2020)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
EGCG affects diabetes-related comorbidities such as diabetic neuropathy.
“to affect diabetes-related comorbidities such as diabetic neuropathy (Raposo et al., 2015)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Raposo et al., 2015 source
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- Premisecitation
EGCG increases α-cleavage of APP.
“experimental studies have provided evidence that EGCG increases the α-cleavage of APP (Rezai-Zadeh et al., 2005; Ettcheto et al., 2020)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
In obese mice, luteolin improves cognitive deficits by alleviating neuroinflammation, oxidative stress and neuronal insulin resistance.
“In obese mice, luteolin improves cognitive deficits by alleviating neuroinflammation, oxidative stress and neuronal insulin resistance (Liu et al., 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2014 source
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- Premisecitation
Combination of luteolin with palmitoylethanolamide reduces iNOS and GFAP expression and protects glial cells against Aβ injury in in vitro and ex vivo models.
“the combination of luteolin with another anti-inflammatory compound, the palmitoylethanolamide is able to reduce iNOS and GFAP expression and protect glial cells against the Aβ injury in both in vitro and ex vivo experimental models (Paterniti et al., 2014)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Paterniti et al., 2014 source
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- Premisecitation
Clinical use of quercetin is limited probably due to poor BBB permeability, low bioavailability, and rapid metabolism.
“a clinical approach with the use of quercetin has been quite limited probably due to its poor permeability of the BBB, low bioavailability, and rapid metabolism (Cai et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cai et al., 2013 source
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- Premisecitation
Luteolin mitigates many pathogenic mechanisms responsible for AD, including neuroinflammatory processes and impairment of brain glucose metabolism.
“Luteolin, a flavone widely distributed in herbs and vegetables, has emerged as an interesting phytochemical able to mitigate many pathogenic mechanisms responsible for AD, including neuroinflammatory processes and the impairment of brain glucose metabolism.”
Quote in the paperSubstantial claim - Premisecitation
EGCG treatment has limitations such as high metabolism and degradation, preventing sufficient concentration in human plasma.
“EGCG treatment displays some limitations such as the high rate of metabolism and subsequent degradation, which in turn prevent a sufficient concentration in human plasma (Pervin et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pervin et al., 2019 source
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- Premisecitation
Quercetin increases expression of SOD and GSH.
“to increase the expression of SOD and GSH (Ishige et al., 2001)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ishige et al., 2001 source
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- Premisecitation
Nanotechnology may significantly improve brain delivery of quercetin and enhance its bioavailability.
“several studies using multiple nanoparticles formulations have shown that the use of nanotechnology may significantly improve the brain delivery of quercetin and enhance its bioavailability (Kumari et al., 2010; Bagad and Khan, 2015; Najafabadi et al., 2018)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
EGCG and its metabolites may exert significant neuroprotective activities.
“Many in vitro and in vivo studies have demonstrated that EGCG and its metabolites may exert significant neuroprotective activities.”
Quote in the paperSubstantial claim - Premisecitation
EGCG can rescue cognitive impairment and Aβ pathology in animal models of AD through anti-inflammatory, antioxidant, and antiaggregating activities.
“A recent meta-analysis of 17 studies performed on animal models of AD has demonstrated that EGCG can rescue cognitive impairment and Aβ pathology through the combination of its anti-inflammatory, antioxidant, and antiaggregating activities (Zhang et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2020 source
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- Premisecitation
Luteolin is a modulator of immune reactions with very efficient anti-inflammatory properties in peripheral macrophages compared to other flavonoids including quercetin.
“Luteolin seems to be a modulator of immune reactions for its very efficient anti-inflammatory properties in peripheral macrophages, compared to those of other flavonoids including its analogue quercetin (Comalada et al., 2006)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Comalada et al., 2006 source
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- Premisecitation
Genistein directly binds Aβ25-35 fragment preventing formation of its aggregates.
“Hirohata et al. (2012) observed that genistein can directly bind the Aβ25-35 fragment preventing the formation of its aggregates.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hirohata et al., 2012 source
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- Premisecitation
EGCG permeates the BBB at low micromolar levels.
“EGCG displays to permeate the BBB at low micromolar levels (Pervin et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pervin et al., 2017 source
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- Premisecitation
Genistein inhibits NF-kB signaling mediated by TLR4.
“genistein can inhibit the activity of NF-kB signal pathway mediated by Toll-like receptor (TLR4) (Zhou et al., 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhou et al., 2014 source
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- Premisenone given
Neuroinflammation causes abnormal secretion of pro-inflammatory cytokines that trigger signaling pathways leading to protein aggregation in AD brain.
“Neuroinflammation is responsible for an abnormal secretion of pro-inflammatory cytokines that trigger detrimental signaling pathways leading to protein aggregation in the AD brain.”
Quote in the paperSubstantial claim - Premisereasoning
Many monoterpenes display free radical scavenging ability arising from conjugated double bonds typical of isoprenoid structure.
“Many monoterpenes display a free radical scavenging ability, which seems to arise from the presence of the conjugated double bonds typical of the isoprenoid structure.”
Quote in the paperSubstantial claim - Premisecitation
Genistein exerts potent antioxidant effects due to numerous phenolic moieties.
“owing to the presence of numerous phenolic moieties in its structure, genistein exerts potent anti-oxidant effects (Gong et al., 2015)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gong et al., 2015 source
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- Premisecitation
In diabetic mice, genistein and some derivatives improve cognitive dysfunction by inhibiting AChE and modulating Ca2+ homeostasis in cholinergic neurons.
“in diabetic mice genistein (Pedersen et al., 1996; Wang et al., 2016), as well as some of its derivatives (Qiang et al., 2014), can improve cognitive dysfunction by inhibiting the activity of AChE and by the modulation of Ca2+ homeostasis in cholinergic neurons (Jhamandas et al., 2001)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisereasoning
Geniposide displays significant neuroprotective potential.
“Geniposide, a major iridoid glycoside of Gardenia jasminoides J. Ellis (Rubiaceae) fruits, displays a significant neuroprotective potential.”
Quote in the paperSubstantial claim - Premisecitation
Curcumin's antioxidant activity derives from its β-diketone structure and phenolic groups, which scavenge free radicals.
“the antioxidant activity of curcumin seems to derive from its β-diketone structure and phenolic groups, which confer the ability to scavenge free radicals (Ak and Gülçin, 2008)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ak and Gülçin, 2008
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- Premisereasoning
Genistein modulates AD pathogenetic mechanisms including Aβ metabolism, inflammation and cholinergic system dysfunction.
“genistein can modulate several pathogenetic mechanisms in AD including Aβ metabolism, inflammation and cholinergic system dysfunction.”
Quote in the paperSubstantial claim - Premisereasoning
Monoterpenes are emerging as potential therapeutic agents in multiple disorders for their antioxidant activity.
“These plant-derived compounds, already known for their very effective antibacterial and antifungal activities, are now emerging as potential therapeutic agents in multiple disorders for their antioxidant activity.”
Quote in the paperSubstantial claim - Premisecitation
Geniposide protects PC12 and SH-SY5Y cells from oxidative damage and apoptosis by modulating MAPK signaling, caspases, and increasing SOD and GPx.
“geniposide has been demonstrated to protect PC12 and SH-SY5Y cells from oxidative damage and apoptotic processes, by modulating the MAPK signaling pathways and caspases expression and by increasing the levels of SOD and GPx (Liu et al., 2006; Liu et al., 2007; Yin et al., 2010a; Yin et al., 2010b; Sun et al., 2013)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Genistein reduces Aβ production by inhibiting BACE-1.
“genistein can reduce the production of Aβ by inhibiting BACE-1 (Youn et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Youn et al., 2018 source
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- Premisecitation
Genistein modulates Aβ-induced increased IL-1β and TNF-α in astrocytes.
“the increased levels of IL-1β and TNF-α induced by Aβ were modulated treating astrocytes with genistein (Valles et al., 2010)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Valles et al., 2010 source
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- Premisecitation
Curcumin-containing nanoliposomes and other delivery systems are very effective in reducing Aβ fibrils formation.
“curcumin-containing nanoliposomes as well as other delivery systems have been designed and show to be very effective in reducing the Aβ fibrils formation (Taylor et al., 2011; Lazar et al., 2013; Mourtas et al., 2014; Shahbaz et al., 2021)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Curcumin exerts neuroprotective effect in neuronal cultures exposed to pro-oxidant conditions by counteracting H2O2 and Fe3+ toxicity.
“In neuronal cultures exposed to pro-oxidant conditions, curcumin exerts a strong neuroprotective effect by counteracting the toxicity of H2O2 and Fe3+ (Morales et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Morales et al., 2017 source
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- Premisecitation
Genistein reduces Aβ1-42-induced neurotoxicity by inhibiting AP180 and RhoA and Aβ accumulation.
“Genistein can reduce the neurotoxicity induced by Aβ1-42 by inhibiting kinesin AP180T (AP180) and Ras homolog family member A (RhoA) and, therefore, Aβ accumulation (Yu et al., 2010)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yu et al., 2010
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- Premisecitation
Curcumin inhibits NF-κB and MAPK activation in LPS-stimulated microglia.
“curcumin has been demonstrated to inhibit NF-κB and MAPK activation in LPS-stimulated microglia (Porro et al., 2019; Zhang et al., 2019)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Curcumin inhibits oxidative damage in PC12 cells exposed to Aβ toxicity.
“In rat pheochromotocytoma cells (PC12) exposed to Aβ toxicity, curcumin has been shown to inhibit oxidative damage (Park et al., 2008)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Park et al., 2008 source
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- Premisecitation
Curcumin improves cognitive functions in AD by reducing oxidative damage, inflammation and Aβ aggregation.
“Growing evidence has demonstrated that curcumin can significantly improve cognitive functions in AD by reducing oxidative damage, inflammation and Aβ aggregation.”
Quote in the paperSubstantial claim - Premisecitation
Curcumin decreases IL-1β, IL-6 and TNF-α expression in Aβ-activated microglia by inhibiting Erk1/2 and p38 MAPK pathways.
“curcumin has been shown to decrease in a concentration-dependent manner the expression of IL-1β, IL-6 and TNF-α in the Aβ-activated microglia by inhibiting Erk1/2 and p38 MAPK pathways (Shi et al., 2015)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Shi et al., 2015 source
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- Premisecitation
Genipin inhibits inflammation by downregulating chemokines, chemokine receptors, and interferon-induced protein expression.
“Besides, genipin has also been shown to inhibit inflammation by downregulating chemokines, chemokine receptors and interferon-induced protein expression (Li et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Li et al., 2012
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- Premisecitation
Catalpol exerts an anti-hyperglycemic effect in STZ-induced diabetic rats.
“Indeed, catalpol exerts an anti-hyperglicemic effect in STZ-induced diabetic rats (Huang et al., 2010) and ameliorates insulin resistance induced by HFD by suppressing the NF-κB pathway (Zhou et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Huang et al., 2010 source
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- Premisecitation
In APP/PS1 mice, geniposide's inhibitory effect on Tau hyperphosphorylation and Aβ1-42 production is due to increased leptin signaling.
“Other studies performed in APP/PS1 have suggested that the inhibitory effect of geniposide on Tau hyperphosphorylation and Aβ1-42 production is due to an increase of leptin signaling (Liu et al., 2015; Liu et al., 2017)”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Genipin decreases Aβ generation in neuronal cells overexpressing the Swedish mutant APP by inhibiting BACE-1 expression.
“Moreover, it has recently been reported that genipin reduces Tau phosphorylation and fibrillation in Tau-overexpressing cells and decreases the Aβ generation in neuronal cells overexpressing the Swedish mutant APP, by inhibiting BACE-1 expression (Li F et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li F et al., 2021
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- Premisecitation
Catalpol interferes with mechanisms underlying diabetes, atherosclerosis, and ischemic injury.
“Catalpol, an iridoid glycoside extracted from the roots of Rehmannia glutinosa (Gaertn.) DC. (Plantaginaceae), has been shown to interfere with different mechanisms underlying many pathological conditions such as diabetes, atherosclerosis, and ischemic injury (Cai et al., 2016; Liu et al., 2016; Xue et al., 2016; Yan et al., 2018; Bai et al., 2019; Chen et al., 2020; He et al., 2021).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Genipin protects neuronal cells against the cytotoxicity of Aβ, H2O2, and rotenone by preventing ROS/RNS-induced damage.
“Genipin has also displayed the ability to protect neuronal cells against the cytotoxicity of Aβ, H2O2 and rotenone by preventing widespread damage induced by the increase of ROS and RNS production (Yamazaki et al., 2001; Hughes et al., 2014).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Genipin exerts strong anti-inflammatory activity in several models of inflammation by targeting iNOS and NF-κB.
“Genipin has been found to exert a strong anti-inflammatory activity in several models of inflammation by targeting iNOS and NF-κB.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Araki et al., 2014 source
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- Premisecitation
Genipin inhibits the increase of NO production and iNOS, COX-2, IL-1β, and IL-6 expression in LPS-activated BV2 microglial cells.
“In particular, it has been demonstrated that genipin inhibits the increase of NO production and iNOS, COX-2, IL-1β and IL-6 expression in LPS-activated BV2 microglial cells (Araki et al., 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Araki et al., 2014 source
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- Premisecitation
Catalpol suppresses neuroinflammation by inhibiting NF-κB activation and reducing iNOS activity in LPS-treated astrocytes and in mice with acute systemic inflammation induced by LPS.
“Several in vitro studies have also shown that catalpol is able to protect astrocytes from H2O2 damage and to suppress neuroinflammation by inhibiting NF-κB activation and reducing iNOS activity in LPS-treated astrocytes and in mice with acute systemic inflammation induced by LPS (Bi et al., 2008; Zhang et al., 2009; Bi et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Bi et al., 2008
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- cites Zhang et al., 2009 source
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- cites Bi et al., 2013
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- Premisecitation
Catalpol ameliorates insulin resistance induced by HFD by suppressing the NF-κB pathway.
“Indeed, catalpol exerts an anti-hyperglicemic effect in STZ-induced diabetic rats (Huang et al., 2010) and ameliorates insulin resistance induced by HFD by suppressing the NF-κB pathway (Zhou et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhou et al., 2015 source
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- Premisecitation
In APP/PS1 transgenic mice, geniposide ameliorates memory deficits by suppressing oxidative damage, mitochondrial function, and MAPK signaling overactivation.
“In APP/PS1 transgenic mice, the treatment with geniposide ameliorates memory deficits by significantly suppressing oxidative damage, mitochondrial function, and MAPK signaling overactivation (Lv et al., 2014; Zhao et al., 2017)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Lv et al., 2014
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- cites Zhao et al., 2017 source
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- Premisecitation
Linalool significantly counteracts cell death and COX-2 increase in organotypic hippocampal slices exposed to NMDA.
“Moreover, linalool significantly counteracts cell death and COX-2 increase in organotypic hippocampal slices exposed to NMDA (Sabogal-Guáqueta et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sabogal-Guáqueta et al., 2019 source
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- Premisecitation
Geniposide counteracts Tau phosphorylation induced by insulin deficiency in STZ-treated AD mice by promoting GSK-3β phosphorylation and inactivation.
“geniposide counteracts the increase of Tau phosphorylation induced by the insulin deficiency in AD mice treated with STZ, by promoting GSK-3β phosphorylation and subsequent inactivation (Zhang et al., 2015)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2015 source
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- Premisecitation
Linalool improves the antioxidant potential of many essential oils by acting in synergy with other components.
“Despite its lower antioxidant activity compared to other monoterpenes due to the lack of conjugated double bonds, linalool has been shown to improve the antioxidant potential of many essential oils by acting in synergy with other components (Wojtunik-Kulesza et al., 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wojtunik-Kulesza et al., 2019 source
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- Premisecitation
Catalpol protects astrocytes from H2O2 damage.
“Several in vitro studies have also shown that catalpol is able to protect astrocytes from H2O2 damage and to suppress neuroinflammation by inhibiting NF-κB activation and reducing iNOS activity in LPS-treated astrocytes and in mice with acute systemic inflammation induced by LPS (Bi et al., 2008; Zhang et al., 2009; Bi et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bi et al., 2008
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- Premisecitation
Lavandula angustifolia and Coriandrum sativum essential oils containing linalool as major component display antioxidant and anti-apoptotic effects.
“In agreement, Lavandula angustifolia and Coriandrum sativum essential oils containing linalool as major component have also displayed antioxidant and anti-apoptotic effects, hence confirming the beneficial potential of linalool in synergistic combination with other components (Caputo et al., 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Caputo et al., 2021 source
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- Interpretationreasoning
Many natural compounds are effective in regulating multiple molecular pathways, making them suitable agents for a multi-target therapeutic approach.
“Intriguingly, a major plus of many natural compounds is their effectiveness in regulating multiple molecular pathways, thus emerging as suitable agents for a multi-target therapeutic approach (Figure 5).”
Quote in the paperSubstantial claim - Premisecitation
The neuroprotective effects of linalool correlate with reduced levels of p38 MAPK, NOS2, COX-2, and IL-1β.
“These neuroprotective effects correlate with reduced levels of p38 MAPK, NOS2, COX-2, and IL-1β (Sabogal-Guáqueta et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sabogal-Guáqueta et al., 2016 source
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- Premisecitation
Limonene exerts anti-AChE activity.
“Like many other monoterpenes, limonene has been found to exert an anti-AchE activity (Szwajgier and Baranowska-Wójcik, 2019; Piccialli et al., 2021).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
The first critical hindrance to the clinical use of natural compounds is the difficulty in extrapolating the dose required in humans from that providing a biological effect in in vitro or in vivo studies.
“The first critical hindrance to the clinical use of natural compounds is the difficulty in extrapolating the dose required in humans from that providing a biological effect in in vitro or in vivo studies.”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical results from human trials of natural compounds in AD have been mostly insufficient or disappointing.
- Interpretationreasoning
The clinical use of many promising plant-derived compounds has proven unsuccessful, especially due to their poor pharmacokinetic profile.
“To date, although preclinical investigations have suggested their neuroprotective potential, the clinical use of many promising plant-derived compounds has proven unsuccessful, especially due to their poor pharmacokinetic profile.”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical results from human trials of natural compounds in AD have been mostly insufficient or disappointing.
- Premisecitation
In a Drosophila model of AD, limonene counteracts Aβ1-42-induced neurotoxicity by decreasing ROS levels and preventing Erk phosphorylation.
“A recent study performed in a Drosophila model of AD has shown that limonene is able to counteract the Aβ1-42-induced neurotoxicity by decreasing ROS levels and hence preventing Erk phosphorylation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shin et al., 2020 source
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- Premisenone given
Many phytochemicals exert significant antioxidant and anti-inflammatory effects.
“In particular, many phytochemicals have been proven to exert significant antioxidant and anti-inflammatory effects.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The discrepancies between pre-clinical research and clinical results suggest that scientific literature may overestimate the potential benefits of natural compounds on cognitive impairment.
“The discrepancies between pre-clinical research and clinical results suggest that scientific literature may probably overestimate the potential benefits of natural compounds on cognitive impairment.”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical results from human trials of natural compounds in AD have been mostly insufficient or disappointing.
- Premisecitation
Limonene suppresses oxidative stress and inflammation by inhibiting COX-2, iNOS, and NF-kB in doxorubicin-treated rats.
“In addition, limonene has been demonstrated to suppress oxidative stress and inflammation by inhibiting COX-2, iNOS, and NF-kB in doxorubicin-treated rats (Rehman et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rehman et al., 2014 source
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- Classified as probably not a substantial claim. 24
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Findingown dataIn vitro results from our laboratory show that linalool counteracts mitochondrial dehydrogenase activity reduction, increase of intracellular ROS, and caspase-3 activation in PC12 cells exposed to Aβ1-42 oligomers.
“In line with these reports, in vitro results from our laboratory have shown that linalool is able to counteract the mitochondrial dehydrogenase activity reduction, increase of intracellular levels of ROS, and caspase-3 activation in PC12 cells exposed to Aβ1-42 oligomers.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAdditional changes in the Alzheimer's disease brain include amyloid angiopathy, neuroinflammation, and significant shrinkage of the hippocampus and entorhinal cortex detectable at MRI.
“Beside these two principal hallmarks, additional changes may be observed, including amyloid deposition at the vascular level (amyloid angiopathy), neuroinflammation, and a significant shrinkage of the hippocampus and enthorinal cortex, detectable at the MRI scan, in comparison to the brain of unaffected people (Serrano-Pozo et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Serrano-Pozo et al., 2014
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InterpretationreasoningAlthough how the complex interplay among different mechanisms contributes to Alzheimer's disease etiology remains poorly understood, a multifactorial hypothesis is probably the most suitable to describe the onset of sporadic AD taking into account aging as the most important risk factor.
“In addition, although how the complex interplay among different mechanisms contribute to the AD etiology remains still poorly understood, a multifactorial hypothesis is probably the most suitable to describe the onset of sporadic AD taking also note of aging as the most important risk factor.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Multiple etiological factors may converge in a common pathological manifestation in Alzheimer's disease.
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Premisenone givenThe formation of Alzheimer's disease lesions develops over two or three decades, resulting in a preclinical period in which AD neuropathology is present without cognitive symptoms.
“The formation of AD lesions develops over two or 3 decades, resulting in a preclinical period in which the AD neuropathology is present without any cognitive symptoms.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe amyloid cascade hypothesis has undergone extensive debate because of its inability to fully describe the complex pathogenesis of Alzheimer's disease and the continuous failure of Aβ-targeted therapies.
“However, the “amyloid cascade hypothesis” has progressively undergone an extensive debate because of its inability to fully describe the complex pathogenesis of AD and the continuous failure of Aβ-targeted therapies.”
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PremisecitationThe most accepted etiological hypothesis of Alzheimer's disease is the amyloid cascade hypothesis, which considers aggregation of Aβ peptide and its accumulation in brain tissues as the main trigger of the AD neurodegenerative cascade.
“At present, the most accepted etiological hypothesis of AD is the so-called “amyloid cascade hypothesis,” which considers the aggregation of the Aβ peptide and its accumulation in brain tissues as the main trigger of the AD neurodegenerative cascade (Selkoe and Hardy, 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Selkoe and Hardy, 2016 source
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PremisecitationApproved drugs for Alzheimer's disease provide only symptomatic relief and are not able to arrest the onset and progression of AD-related neurodegeneration.
“the few drugs approved for the AD treatment are only limited to a slight relief of symptoms but are not able to arrest the onset and progression of the AD-related neurodegeneration (Husna Ibrahim et al., 2020; Jeremic et al., 2021).”
- Also stated in: § Abstract · hedged
“the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Husna Ibrahim et al., 2020
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- cites Jeremic et al., 2021 source
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PremisecitationAPP is a large transmembrane protein physiologically undergoing non-amyloidogenic processing consisting in sequential cleavage by α- and γ-secretases.
“The APP, which has been reported to be involved in many important physiological functions of neurons (Priller et al., 2006), is a large transmembrane protein physiologically undergoing a non-amyloidogenic processing consisting in the sequential cleavage by α- and γ-secretases (Selkoe, 2002).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Priller et al., 2006
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- cites Selkoe, 2002
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PremisecitationIncreasing age is the major non-genetic risk factor for Alzheimer's disease, with genetic and environmental factors influencing onset and severity.
“The increasing age is instead considered the major non-genetic risk factor, with genetic and environmental factors influencing the onset and severity of the disease (Zhang et al., 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang et al., 2021
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Premisenone givenMany strategies have been conceived to overcome limitations of some promising phytochemicals related to poor pharmacokinetic profiles, including nanotechnology and synthetic routes.
“Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNon-dominant genetic factors account for most cases of late-onset familial Alzheimer's disease.
“Regarding the late-onset forms of familial AD, non-dominant genetic factors have been found to account for most of the cases (Kwok et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kwok et al., 2020
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Interpretationnone givenRodent models of Alzheimer's disease, despite replicating some AD symptoms and being useful for testing anti-AD drugs, are not sufficient for modeling the complexity of AD pathology and are incapable of explaining the origins of sporadic AD.
“These models, despite replicating some AD symptoms and being useful for testing the efficacy of anti-AD drugs, are not sufficient for modeling the complexity of the AD pathology and, importantly, are incapable to explain the origins of the sporadic forms of AD.”
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PremisecitationThe most abundant Aβ species are Aβ1-40 and Aβ1-42, with Aβ1-42 being the most prone to aggregate into β-sheet structures and hence the most toxic.
“The most abundant species are the Aβ1-40 and Aβ1-42 (Seubert et al., 1993), the latter being the most prone to aggregate into structures with a β-sheet conformation and, hence, the most toxic (Bressler et al., 1996; Folch et al., 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Seubert et al., 1993
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- cites Bressler et al., 1996
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- cites Folch et al., 2018
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PremisecitationLittle is known about the origins of Aβ deposition and neurodegeneration in sporadic Alzheimer's disease, which represents the greatest proportion of all AD cases.
“By contrast, still little is known about the origins of the Aβ deposition and neurodegeneration occurring in the sporadic AD, which represents the greatest proportion of all AD cases (Efthymiou and Goate, 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Efthymiou and Goate, 2017 source
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Premisenone givenMany plant-derived compounds have proven efficacy in counteracting several pathogenic processes such as Aβ aggregation, neuroinflammation, oxidative stress, and insulin resistance.
“Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningPhytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting traditional pharmacological medicine.
“In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine.”
- Also stated in: § Introduction · plain
“In this context, plant-derived compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine.”
Quote in the paperNot a substantial claim- Also stated in: § Introduction · plain
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Premisenone givenMuch information about pathological features of Alzheimer's disease arises from numerous genetic and toxin-induced rodent models of AD developed in the last decades.
“In this regard, it is worth noting that much information about the pathological features of AD arises from the numerous genetic and toxin-induced rodent models of AD that have been developed in the last decades.”
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PremisecitationInheritance of the ε4 allele of APOE is associated with increased Aβ deposition and tau pathology, constitutes the strongest genetic risk factor for sporadic Alzheimer's disease, and influences age at onset and progression.
“Nonetheless, the inheritance of the ε4 allele of the Apolipoprotein (APO) E gene, which is associated with both increased Aβ deposition and tau pathology (Shi et al., 2017; Shi et al., 2021), constitutes the strongest genetic risk factor for sporadic AD, determining the age at onset of the disease and strictly influencing its progression (Cerf et al., 2011; Hashimoto et al., 2012; Koffie et al., 2”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Shi et al., 2017 source
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- cites Shi et al., 2021
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- cites Cerf et al., 2011
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Premisenone givenSeveral other hypotheses of Alzheimer's disease have been proposed, including impairment of cholinergic transmission, mitochondrial dysfunction, oxidative stress, neuroinflammation, and brain insulin resistance.
“Meanwhile, several other hypotheses have been proposed, including those centered on the impairment of cholinergic transmission, mitochondrial dysfunction, oxidative stress, neuroinflammation, and brain insulin resistance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAccording to the amyloid cascade hypothesis, intracellular and extracellular deposition of Aβ aggregates triggers a sequence of deleterious events including gliosis, oxidative stress, Tau hyperphosphorylation, neuronal death, and synaptic loss.
“According to this hypothesis, the intracellular and extracellular deposition of Aβ aggregates triggers a sequence of deleterious events that contribute to the AD pathogenesis, including gliosis, oxidative stress, Tau hyperphosphorylation, neuronal death, and synaptic loss (Braak and Braak, 1994).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Braak and Braak, 1994
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PremisecitationMutations in APP, PS1, and PS2 genes induce aberrant processing of APP and consequent increase of Aβ production, and are main determinants of early-onset autosomal dominant Alzheimer's disease.
“Three genes whose mutations induce an aberrant processing of the amyloid precursor protein (APP) and the consequent increase of the Aβ production, the APP, Presenilin 1 (PS1) and Presenilin 2 (PS2) genes, have been identified as the main determinants of the early-onset autosomal dominant AD (Serretti et al., 2007; Fernandez et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Serretti et al., 2007
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- cites Fernandez et al., 2014
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PremisereasoningMuch interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing modifiable risk factors associated with aging.
“As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging.”
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PremisecitationHigh levels of sporadic mutations in mitochondrial DNA were found in Alzheimer's disease brains along with deficiencies in mitochondrial DNA repair mechanisms.
“In particular, high levels of sporadic mutations in mitochondrial DNA were found in AD brains along with deficiencies in mitochondrial DNA repair mechanisms (Lin et al., 2002; Singh et al., 2015; Nissanka and Moraes, 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Lin et al., 2002
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- cites Singh et al., 2015
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- cites Nissanka and Moraes, 2018
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PremisecitationIn secondary nucleation, fibrils act as a catalytic surface for the formation of new aggregates.
“In an alternative aggregation pathway known as secondary nucleation, the fibrils act as a catalytic surface for the formation of new aggregates (Arosio et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Arosio et al., 2015
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PremisecitationSoluble Aβ aggregates spreading throughout the brain may form insoluble deposits at the vascular level and compromise vascular function and blood-brain barrier integrity.
“the soluble Aβ aggregates spreading throughout the brain may in fact form insoluble deposits at the vascular level and compromise the vascular function and BBB integrity (Xu et al., 2016; Soto-Rojas, et al., 2021).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Xu et al., 2016
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- cites Soto-Rojas, et al., 2021
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PremisecitationActivation of the JNK pathway induces caspase activation, further promoting Tau cleavage.
“Interestingly, the activation of the JNK pathway induces caspase activation, further promoting Tau cleavage (Sahara et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sahara et al., 2008
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PremisecitationTau, the main component of neurofibrillary tangles, is a microtubule stabilizer protein that normally undergoes post-translational modifications including phosphorylation.
“Tau, the main component of NFTs, is a microtubule stabilizer protein that normally undergoes a myriad of post-translational modifications, including phosphorylation (Goodson and Jonasson, 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Goodson and Jonasson, 2018
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PremisecitationTau induces a pro-inflammatory response in microglia by activating p38 MAPK, whose blockade promotes microglial phagocytic function and reverses Tau toxicity.
“Nonetheless, very recently it has been demonstrated that Tau induces a pro-inflammatory response in microglia by activating p38 MAPK, whose blockade, instead, promotes microglial phagocytic function and reverses Tau toxicity (Perea et al., 2018; Perea et al., 2022).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Perea et al., 2018
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- cites Perea et al., 2022
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PremisecitationTau can affect mitochondrial function by inducing ROS production, reducing mitochondrial respiration, and impairing mitochondrial transport along neuronal axons.
“Importantly, Tau can affect mitochondrial function by inducing ROS production, reducing mitochondrial respiration and causing the impairment of mitochondrial transport along neuronal axons (David et al., 2005; Dubey et al., 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites David et al., 2005
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- cites Dubey et al., 2008
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PremisecitationBoth Aβ1-40 and Aβ1-42 interact with several receptors including NMDA, AMPA, nACh, and mACh receptors, and induce synaptic transmission impairment through Ca2+ dysregulation and blockage of ion channels and neurotransmitters.
“Both Aβ1-40 and Aβ1-42 have been shown to interact with several receptors including the N-Methyl-D-Aspartate (NMDA), α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic acid (AMPA), nicotinic Acetylcholine (nACh), and muscarinic Acetylcholine (mACh) receptors (Tozaki et al., 2002; Snyder et al., 2005; Liskowsky and Schliebs, 2006; Gu et al., 2009), and to induce a synaptic transmission impairment”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Tozaki et al., 2002
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- cites Snyder et al., 2005 source
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- cites Peña et al., 2006
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PremisecitationAβ triggers activation of caspase-3 and calpain-1, which can cleave Tau at the C-terminus generating small fragments able to induce neurite degeneration and neuronal death.
“Moreover, Aβ triggers the activation of caspase-3 and calpain-1, which can cleave Tau at the C-terminus generating small fragments able to induce neurite degeneration and neuronal death (Gamblin et al., 2003; Bloom, 2014; Chen et al., 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationDissociation from microtubules and formation of neurofibrillary tangles cause impairment of axonal transport, cytoskeletal and mitochondrial dysfunction, oxidative stress, and synaptic loss, and increase cytosolic tau further promoting its aggregation and fibrillization.
“The dissociation from microtubules and the formation of NFTs in turn cause the impairment of the axonal transport, cytoskeletal and mitochondrial dysfunction, oxidative stress, and synaptic loss (Hoover et al., 2010) and, moreover, increase the cytosolic content of tau further promoting its aggregation and fibrillization.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hoover et al., 2010 source
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PremisecitationTau hyperphosphorylation leads to its aggregation and dissociation from microtubules.
“Tau hyperphosphorylation leads to its aggregation and dissociation from microtubules (Wang et al., 2013; Gao et al., 2018).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Wang et al., 2013
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- cites Gao et al., 2018
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PremisecitationType 2 diabetes mellitus is a complex chronic disorder highly prominent in older people, characterized by chronic increase in blood glucose levels, impaired insulin secretion by pancreatic β-cells, and insulin resistance.
“T2DM is a complex chronic disorder highly prominent in older people, characterized by the chronic increase in blood glucose levels, impaired insulin secretion by pancreatic β-cells, and insulin resistance (DeFronzo et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites DeFronzo et al., 2015 source
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PremisecitationSeveral studies reported high levels of inflammatory markers in the brain of Alzheimer's disease patients, elevated levels of cytokines and chemokines in serum and cerebrospinal fluid, and microgliosis.
“Accordingly, several studies reported high levels of inflammatory markers in the brain of AD patients, elevated levels of cytokines and chemokines in serum and cerebrospinal fluid, and microgliosis (Zhang F et al., 2013; Dursun et al., 2015; Hesse et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Zhang F et al., 2013
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- cites Dursun et al., 2015 source
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- cites Hesse et al., 2016
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PremisecitationAβ oligomers induce an increase of intracellular Ca2+ levels promoting its accumulation in mitochondria, which induces opening of mPTP, release of mitochondrial ROS, and apoptotic cell death.
“Furthermore, Aβ oligomers induce an increase of intracellular Ca2+ levels promoting its accumulation in mitochondria (Calvo-Rodriguez et al., 2019), which in turn induces the opening of the mPTP, release of mitochondrial ROS, and apoptotic cell death (Esteras and Abramov, 2020).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Calvo-Rodriguez et al., 2019
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- cites Esteras and Abramov, 2020
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PremisecitationNF-κB is responsible for activation of uncontrolled microglia, with subsequent ROS production, and pro-inflammatory cytokine and glutamate release, which induce neuronal damage.
“NF-κB is responsible for the activation of uncontrolled microglia, with subsequent ROS production, and pro-inflammatory cytokine and glutamate release, which in turn induce neuronal damage (Spencer et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Spencer et al., 2012 source
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PremisecitationDespite its ability to uptake glucose in an insulin-independent manner, the brain is an insulin-sensitive organ widely expressing insulin receptors, especially in regions crucial for cognition and feeding.
“Despite its ability to uptake glucose in an insulin-independent manner, the brain is in fact an insulin-sensitive organ widely expressing insulin receptors (IR), especially in those regions considered crucial for cognition and feeding (Milstein and Ferris, 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milstein and Ferris, 2021
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PremisecitationOxidizing agents can increase the expression of APP and the expression and activity of BACE-1.
“Indeed, it was shown that oxidizing agents can increase the expression of the APP (McCarty et al., 2021), and the expression and activity of BACE-1 (Tamagno et al., 2002; Tong et al., 2005; Zhang et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites McCarty et al., 2021
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- cites Tamagno et al., 2002
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- cites Tong et al., 2005
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PremisecitationBoth oxidative stress and mitochondrial failure have been linked to Aβ, although it is unclear whether Aβ aggregation and accumulation are predominantly the cause or consequence of oxidative stress.
“At molecular level, both oxidative stress and mitochondrial failure have been linked to Aβ, although it is still unclear whether the Aβ aggregation and accumulation are predominantly the cause or rather a consequence of oxidative stress (Cheignon et al., 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cheignon et al., 2018 source
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PremisecitationDeterioration of systemic glucose metabolism, ranging from chronic mild glucose intolerance to type 2 diabetes mellitus, is present before clinical appearance of sporadic Alzheimer's disease, suggesting early severe brain hypometabolism may contribute to neuropathological changes leading to AD.
“The deterioration of systemic glucose metabolism, which may range from chronic, mild glucose intolerance to type 2 diabetes mellitus (T2DM), has been found to be present before the clinical appearance of sporadic AD, hence suggesting that an early and severe brain hypometabolism may contribute to the neuropathological changes leading to AD (Cunnane et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cunnane et al., 2011
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PremisecitationHigh fat diet feeding, obesity, and type 2 diabetes mellitus are the main causes of insulin resistance and are all recognized as risk factors for late-onset Alzheimer's disease.
“High fat diet (HFD) feeding, obesity and T2DM are the main causes of insulin resistance and are all recognized as risk factors for late-onset AD (Terzo et al., 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Terzo et al., 2021
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InterpretationcitationIncreased leakage from the blood-brain barrier may impair Aβ clearance and lead to microglial activation, amplifying the inflammatory response.
“The increased leakage from the BBB may impair the Aβ clearance and lead to microglial activation, hence amplifying the inflammatory response (Janota et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Janota et al., 2016
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PremisecitationThe neuroinflammatory process is characterized by activation of glial cells, especially astrocytes and microglia, which trigger release of cytokines and chemokines such as IL-1β and IL-6, and other pro-inflammatory mediators including NF-κB, NO, TNF-α, TNF-β, adhesion molecules, and COX-2.
“The neuroinflammatory process is characterized by the activation of glial cells, especially astrocytes and microglia that, once activated, trigger the release of cytokines and chemokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6), and other pro-inflammatory mediators including the nuclear factor-κB (NF-κB), nitric oxide (NO), tumor necrosis factor (TNF)-α, TNF-β, adhesion molecules, a”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Akiyama et al., 2000 source
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PremisecitationNatural inhibitors can target Aβ monomer assembly, Aβ oligomer remodeling, and secondary nucleation inhibition.
“the action of natural inhibitors can be directed to 1) the assembly of Aβ monomers, producing small aggregates; 2) the remodeling of Aβ oligomers, leading to the formation of off-pathway species; 3) the inhibition of the secondary nucleation (Najarzadeh et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Najarzadeh et al., 2019
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PremisecitationDietary polyphenols interfere with AD-related pathomechanisms and slow age-related cognitive deficits, reducing dementia risk.
“dietary polyphenols, such as those found in the Mediterranean diet, to interfere with different AD-related pathomechanisms and to slow down age-related cognitive deficits hence reducing the risk of dementia”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Casamenti and Stefani, 2017
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- cites Bagetta et al., 2020
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Premisenone givenThe pharmacological agents currently used for therapy of Alzheimer's disease-associated dementia comprise three acetylcholinesterase inhibitors, donepezil, rivastigmine, and galantamine, and memantine, an NMDA receptor antagonist.
“The pharmacological agents currently used for the therapy of the AD-associated dementia comprise three acetylcholinesterase (AChE) inhibitors, donezepil, rivastigmine, and galantamine (Figure 2). The only non-AChE inhibitor drug, memantine, is a NMDA receptor antagonist (Figure 2).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBrain insulin resistance induces impairment of mitochondrial metabolism and subsequently reduction of ATP production, mitochondrial dyshomeostasis, and increased ROS production.
“For this reason, brain insulin resistance induces the impairment of mitochondrial metabolism and, subsequently, the reduction of the ATP production, mitochondrial dyshomeostasis and increased ROS production (Sripetchwandee et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sripetchwandee et al., 2018
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PremisecitationFlavonoid consumption may ameliorate AD pathology and provide symptomatic benefit due to anti-inflammatory and antioxidant activities.
“Epidemiological studies indicate that the consumption of flavonoids, a large family of polyphenol compounds, may ameliorate the AD pathology and provide a symptomatic benefit especially due to their anti-inflammatory and antioxidant activities”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Devi et al., 2021
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- cites Hole and Williams, 2021
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PremisecitationImpairment of insulin signaling induces increased activation of GSK-3β, which phosphorylates Tau, leading to Tau hyperphosphorylation.
“In addition, the impairment of insulin signaling induces an increased activation of GSK-3β, which phosphorylates Tau, hence leading to Tau hyperphosphorylation (Hong and Lee, 1997; Planel et al., 2007; Zhang et al., 2018; Wei et al., 2021).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Hong and Lee, 1997
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- cites Planel et al., 2007
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- cites Zhang et al., 2018 source
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PremisecitationIn the brain of Alzheimer's disease patients, insulin receptors and IGF-1 receptors are significantly reduced along with a decrease of many components of the insulin signaling cascade.
“In the brain of AD patients, IRs and IGF-1 receptors were found to be significantly reduced along with a decrease of many components of the insulin signaling cascade (Steen et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Steen et al., 2005 source
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PremisecitationRivastigmine is an FDA-approved cholinesterase inhibitor recommended for mild-to-moderate AD.
“Rivastigmine, instead, is a semi-synthetic drug approved by the FDA as a cholinesterase inhibitor recommended for mild-to-moderate AD (Marucci et al., 2021)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Marucci et al., 2021 source
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PremisecitationType 2 diabetes mellitus is associated with hyperlipidaemia, resulting from use of lipids instead of glucose, and subsequent microvascular and macrovascular complications.
“T2DM is also associated to hyperlipidaemia, resulting from the use of lipids instead of glucose, and to subsequent microvascular and macrovascular complications (Vesa et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vesa et al., 2020
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Premisenone givenAll these drugs are used in clinical practice for mild to severe dementia and provide symptomatic relief alleviating to some extent cognitive symptomatology.
“All these drugs are used in clinical practice for mild to severe dementia and provide a symptomatic relief alleviating to some extent the cognitive symptomathology.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationObesity may induce brain insulin resistance through mechanisms including adipose tissue inability to store fatty acids leading to their accumulation in brain, pro-inflammatory macrophages producing cytokines that cross the blood-brain barrier and induce central inflammation, and nutrient overload causing mitochondrial dysfunction and oxidative stress.
“Obesity may induce brain insulin resistance through several mechanisms: 1) in obesity conditions the adipose tissue loses its ability to store fatty acids, thereby inducing their accumulation in other tissues including the brain, which consequently develop insulin resistance (Engin, 2017); 2) in the adipose tissue of obese people, macrophages become pro-inflammatory and produce inflammatory”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
InterpretationreasoningThis evidence has prompted the search for effective disease-modifying agents.
“This evidence has prompted the search for effective disease-modifying agents.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationObesity is a multifactorial disorder of energy metabolism often associated with dyslipidemia, hypertension, and stroke.
“Obesity is a multifactorial disorder of energy metabolism often associated with other pathological conditions including dyslipidemia, hypertension, and stroke (Hall et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hall et al., 2015
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PremisecitationThe brain preferentially expresses insulin-insensitive glucose transporters 1 and 3, while insulin-sensitive glucose transporter 4 is limited to specific brain regions such as the hippocampus and hypothalamus.
“Although there is evidence supporting some roles of insulin in regulating the brain glucose uptake, it is well known that the brain preferentially expresses the insulin-insensitive glucose transporters 1 and 3, while the insulin-sensitive glucose transporter 4 (GLUT4) is limited to specific brain regions such as the hippocampus and hypothalamus (Leloup et al., 1996; Reno et al., 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Leloup et al., 1996
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- cites Reno et al., 2017
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PremisecitationGalantamine is included in AD therapy for cholinesterase inhibitory properties and ability to enhance cholinergic function and ameliorate memory deficits.
“galantamine, a tertiary alkaloid first isolated from Galanthus nivalis L. (Amaryllidaceae), is currently included in the AD therapy for its cholinesterase inhibitory properties and its ability to enhance the cholinergic function and ameliorate memory deficits”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Heinrich, 2010
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- cites Anand and Singh, 2013
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PremisecitationTramiprosate and colostrinin showed promising early clinical results but failed to display efficacy.
“Two drugs able to inhibit the Aβ aggregation, tramiprosate and colostrinin, showed promising results in the early phases of clinical trials to fail successively in displaying any efficacy (Bilikiewicz and Gaus, 2004; Aisen et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Bilikiewicz and Gaus, 2004
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- cites Aisen et al., 2007
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PremisecitationFlavonoids display low circulating concentration compared to well-characterized ROS scavengers, suggesting their antioxidant potential may be due to modulation of intracellular pathways involved in oxidative stress.
“flavonoids display a low circulating concentration if compared to well-characterized ROS scavengers, hence suggesting that their antioxidant potential could be due to different mechanisms such as the modulation of intracellular pathways involved in oxidative stress (Reiber et al., 1993; Borges et al., 2018)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Reiber et al., 1993
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- cites Borges et al., 2018
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PremisecitationChronic resveratrol use in elderly subjects selectively improves psychomotor speed without significantly ameliorating memory function.
“the chronic use of resveratrol selectively improves psychomotor speed without significantly ameliorate memory function (Anton et al., 2018)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Anton et al., 2018
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PremisecitationResveratrol inhibits Aβ aggregation from lower MW oligomers into higher MW oligomers and disrupts pre-formed Aβ aggregates.
“resveratrol is able to inhibit the Aβ aggregation from lower molecular weight (MW) oligomers into higher MW oligomers and to disrupt pre-formed Aβ aggregates (Fu et al., 2014; Ghobeh et al., 2014)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Fu et al., 2014
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- cites Ghobeh et al., 2014
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PremisecitationPolyphenols counteract main pathophysiological mechanisms of T2DM, offering potential benefits for reducing risk of both diabetes and AD.
“many natural substances, especially polyphenols, have been shown to be effective in counteracting the main pathophysiological mechanisms of T2DM hence offering potential benefits for reducing the risk of both diabetes and AD (Blahova et al., 2021)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blahova et al., 2021
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PremisecitationResveratrol improves cognition and reduces amyloid plaque formation in Tg6799 mice.
“resveratrol is able to improve cognition and reduce amyloid plaque formation in Tg6799 mice (Chen et al., 2019)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2019
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PremisecitationFlavonoid intake is correlated with improvement of cognition, attenuation of neuroinflammation and oxidative stress.
“many studies have correlated flavonoid intake with the improvement of cognition, attenuation of neuroinflammation and oxidative stress (Cichon et al., 2021)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cichon et al., 2021
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PremisecitationResveratrol treatment in STZ-injected diabetic rats counteracts oxidative stress, inflammation and synaptic loss, and prevents memory impairment by modulating cholinergic transmission.
“the treatment with resveratrol in streptozotocin (STZ)-injected diabetic rats has been able to counteract many pathogenic mechanisms, including oxidative stress, inflammation and synaptic loss, and to prevent memory impairment by modulating cholinergic transmission (Tian Z. et al., 2016; Tian et al., 2016 Y.)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Tian Z. et al., 2016
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- cites Tian et al., 2016 Y.
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PremisecitationQuercetin improves cognitive function and reduces Aβ plaques and Tau phosphorylation in APP/PS1 mouse model of AD.
“positive effect on cognitive function in APP/PS1 mouse model of AD, where it also reduces Aβ plaques and Tau phosphorylation (Lv et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lv et al., 2018
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PremisecitationIn 3xTg-AD mice, quercetin decreases extracellular Aβ, improves astrogliosis and microgliosis, and preserves cognitive function.
“In 3xTg-AD mice, quercetin decreases the amount of the extracellular Aβ, improves astrogliosis and microgliosis, and preserves cognitive function (Sabogal-Guáqueta et al., 2015; Barreca et al., 2016)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Sabogal-Guáqueta et al., 2015
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- cites Barreca et al., 2016
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PremisecitationResveratrol treatment in patients with mild-to-moderate AD decreases Aβ levels in cerebrospinal fluid and reduces neuroinflammation biomarkers.
“the treatment with resveratrol of patients with mild-to-moderate AD induced a decrease of Aβ levels in cerebrospinal fluid and a reduction of neuroinflammation biomarkers (Moussa et al., 2017)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Moussa et al., 2017
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PremisecitationResveratrol decreases insoluble Aβ in hippocampus of AD rats and has positive effects on BBB integrity.
“to decrease the amount of insoluble Aβ in the hippocampus of AD rats, with positive effects on BBB integrity (Zhao et al., 2015)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhao et al., 2015
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PremisecitationNano-encapsulation of flavonoids may overcome pharmacokinetic limitations and improve bioavailability.
“many studies demonstrated that nano-incapsulation of flavonoids may overcome pharmacokinetic limitations and improve their bioavailability”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationPhenolic moieties can establish π-π stacking with aromatic residues of Aβ or hydrophobic/hydrogen bonding interactions through phenolic hydroxyl groups.
“the phenolic moieties can establish π-π stacking with the aromatic residue of the Aβ or establish hydrophobic or hydrogen bonding interactions through phenolic hydroxyl groups (Fan et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fan et al., 2020
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PremisecitationQuercetin inhibits Aβ aggregation by destabilizing oligomeric species of misfolded proteins and inhibiting fibril growth.
“Quercetin has been proven to effectively inhibit the Aβ aggregation by destabilizing the oligomeric species of misfolded proteins and inhibiting the fibril growth (Matsuzaki et al., 2007)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Matsuzaki et al., 2007
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PremisecitationLuteolin suppresses pro-inflammatory and pro-apoptotic genes in a dose-dependent manner, shifting microglial transcriptome toward anti-inflammatory phenotype.
“the ability of luteolin to suppress in a dose-dependent manner the expression of pro-inflammatory and pro-apoptotic genes hence shifting the microglial transcriptome toward an anti-inflammatory phenotype (Dirscherl et al., 2010)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dirscherl et al., 2010
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PremisecitationQuercetin reduces blood glucose levels, increases plasma insulin levels, and positively affects memory and learning in STZ-induced diabetic rats.
“quercetin reduces blood glucose levels, increases plasma insulin levels and positively affects memory and learning functions in streptozocin (STZ)-induced diabetic rats (Khaki et al., 2010; Srinivasan et al., 2018; Yang and Kang, 2018)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Khaki et al., 2010
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- cites Srinivasan et al., 2018
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- cites Yang and Kang, 2018
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PremisecitationEGCG binds weakly and non-specifically to Aβ monomers while displaying higher affinity toward oligomers.
“EGCG can bind weakly and in a non-specific manner to Aβ monomers while it displays higher affinity toward oligomers (Ahmed et al., 2017)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ahmed et al., 2017
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PremisecitationEGCG inhibits Aβ secondary nucleation and intervenes in early steps of Aβ aggregation inducing spherical, off-pathway aggregates.
“ECGC can inhibit the Aβ secondary nucleation and intervene in the early steps of the Aβ aggregation inducing the formation of spherical, off-pathway aggregates. (Ehrnhoefer et al., 2008; Ahmed et al., 2017)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Ehrnhoefer et al., 2008
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- cites Ahmed et al., 2017
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PremisecitationLuteolin reduces iNOS and COX-2 expression and downregulates pro-inflammatory cytokines and NO production in LPS-activated microglia.
“luteolin exerts an anti-inflammatory effect also in LPS-activated microglia where it has been found to significantly reduce the expression of iNOS and COX-2 and to downregulate pro-inflammatory cytokines and the production of NO (Zhu et al., 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhu et al., 2011
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PremisecitationEGCG treatment improves insulin sensitivity and memory deficits in APP/PS1 mice fed with HFD.
“EGCG treatment improves insulin sensitivity and memory deficits in APP/PS1 mice fed with a HFD (Ettcheto et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ettcheto et al., 2020
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PremisecitationLuteolin improves memory deficits in a mouse model of AD by inhibiting astrocyte overactivation and neuroinflammation and reducing ER stress.
“luteolin is able to improve memory deficits in a mouse model of AD by inhibiting astrocyte overactivation and neuroinflammation and by reducing endoplasmic reticulum (ER) stress (Kou et al., 2021)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kou et al., 2021
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PremisecitationEGCG increases glucose tolerance and glucose-stimulated insulin secretion in obese mice.
“EGCG is able to increase glucose tolerance and the glucose-stimulated insulin secretion in obese mice (Ortsäter et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ortsäter et al., 2012
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PremisecitationEGCG reduces TNF-α, IL-1β, IL-6, and iNOS levels and rescues neurogenesis through mechanisms involving NF-κB.
“EGCG has also displayed an anti-inflammatory activity in several studies by reducing TNF-α, IL-1β, IL-6, and iNOS levels and rescuing neurogenesis through mechanisms involving NF-κB (Cheng-Chung Wei et al., 2016; Seong et al., 2016)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Cheng-Chung Wei et al., 2016
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- cites Seong et al., 2016
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PremisecitationEGCG exerts positive effect on cognitive function by promoting ROS scavenging and counteracting Aβ-induced mitochondrial apoptotic processes.
“EGCG exerts a positive effect on cognitive function by promoting ROS scavenging (Schroeder et al., 2009) and counteracting the Aβ-induced mitochondrial apoptotic processes (Fukutomi et al., 2021)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Schroeder et al., 2009
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- cites Fukutomi et al., 2021
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PremisecitationGeniposide exerts antioxidant and anti-apoptotic effects.
“First, geniposide exerts both antioxidant and anti-apoptotic effects.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCurcumin and its derivatives intercalate among Aβ chains in first stage of Aβ aggregation and form hydrogen bonding and hydrophobic interactions, leading to more disordered amyloid structures.
“curcumin and its derivatives are able to intercalate among Aβ chains in the first stage of the Aβ aggregation and to form hydrogen bonding and hydrophobic interactions with the Aβ peptide, leading to more disordered amyloid structures (Doytchinova et al., 2020)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Doytchinova et al., 2020
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCurcumin delays T2DM by improving β-cell function and reducing insulin resistance.
“to delay T2DM by improving β-cell function and reducing insulin resistance (Chuengsamarn et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chuengsamarn et al., 2012
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PremisecitationPoor BBB passage and very low oral bioavailability explain curcumin's lack of clinical efficacy.
“This evidence has been explained with its poor ability to pass the BBB and its very low oral bioavailability (Begum et al., 2008)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Begum et al., 2008 source
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PremisecitationCurcumin inhibits formation of Aβ1-40 and Aβ1-42 fibrils in vitro in a dose-dependent manner and destabilizes preformed fibrils.
“curcumin inhibits the formation of Aβ1-40 and Aβ1-42 fibrils in vitro in a dose-dependent manner and destabilizes preformed fibrils (Ono et al., 2004; Yang et al., 2005; Hamaguchi et al., 2010)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Ono et al., 2004
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- cites Yang et al., 2005 source
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- cites Hamaguchi et al., 2010
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PremisecitationCurcumin ameliorates neuroinflammation and cognitive decline upon LPS exposure in an animal model of AD.
“the treatment with curcumin ameliorates neuroinflammation and cognitive decline upon exposure to LPS (Sorrenti et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sorrenti et al., 2018
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PremisecitationCurcumin as such in clinical studies does not display significant efficacy against AD, although well-tolerated.
“the use of curcumin as such in clinical studies does not display a significant efficacy against AD, although the drug is well-tolerated (Ringman et al., 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ringman et al., 2012
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PremisecitationCurcumin binds monomeric species and low MW oligomers and induces major structural changes in Aβ1-42 aggregates.
“curcumin is able to bind monomeric species and low MW oligomers (Fu et al., 2014) and to induce major structural changes in the Aβ1-42 aggregates (Mithu et al., 2014)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Fu et al., 2014
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- cites Mithu et al., 2014
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PremisereasoningMonoterpenes have anti-inflammatory, anti-cholinesterase, and anti-nociceptive activities, highlighting therapeutic potential in neurodegenerative diseases including AD.
“the growing knowledge about supplementary activities of monoterpenes such as anti-inflammatory, anti-cholinesterase, and anti-nociceptive activities, is highlighting their therapeutic potential in several neurodegenerative diseases including AD.”
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PremisecitationCurcumin analogues with improved aqueous solubility, pharmacokinetics, bioavailability and stability have been synthesized and show greater efficacy than curcumin.
“many curcumin analogues with improved aqueous solubility, pharmacokinetics, bioavailability and stability have been synthesized. Importantly, these compounds show greater efficacy than curcumin hence appearing as promising agents for the AD treatment (Anand et al., 2008; Airoldi et al., 2011; Yanagisawa et al., 2011)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Anand et al., 2008
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- cites Airoldi et al., 2011
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- cites Yanagisawa et al., 2011
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PremisecitationSystemic curcumin reduces pre-existing plaques in ∼8-month-old APPswe/PS1dE9 mice, suggesting ability to disaggregate Aβ deposits.
“in vivo studies have shown that the systemic treatment with curcumin reduces pre-existing plaques in ∼8-month-old APPswe/PS1dE9 mice, suggesting its ability to disaggregate Aβ deposits (Garcia-Alloza et al., 2007)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Garcia-Alloza et al., 2007
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Premisenone givenGenistein potentially inhibits tyrosine protein kinases and DNA topoisomerases.
“genistein potentially inhibits the activity of tyrosine protein kinases and of a DNA topoisomerases.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationGenistein blocks NF-kB binding to DNA, antagonizing neuroinflammatory effect in AD.
“genistein blocks the binding of NF-kB to the DNA thus antagonizing the neuroinflammatory effect in AD (Seo et al., 2018)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Seo et al., 2018 source
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PremisecitationCurcumin increases insulin receptor activity in rats and activates insulin pathways.
“curcumin has been demonstrated to increase the activity of insulin receptors in rats and activate insulin pathways (Li et al., 2010)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Li et al., 2010
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PremisecitationCatalpol reduces BBB damage and hyperpermeability induced by Aβ1-42 fibrils and increases Aβ clearance.
“In addition, it has been shown that catalpol is able to reduce the BBB damage and subsequent hyperpermeability induced by Aβ1-42 fibrils and to increase the Aβ clearance (Liu et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2018
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PremisecitationCatalpol promotes the activity of endogenous antioxidant enzymes and decreases ROS and NOS production.
“Catalpol has also been found to promote the activity of endogenous antioxidant enzymes and decrease ROS and NOS production (Zhang et al., 2007; Zhang X. et al., 2008; Zhang X. L. et al., 2008; Zhang et al., 2010; Zhang X et al., 2013).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Zhang et al., 2007
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- cites Zhang X. et al., 2008
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- cites Zhang X. L. et al., 2008
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PremisecitationLinalool counteracts the increase of ROS production and mitochondrial Ca2+ levels, preserves mitochondrial integrity, and reduces lipid peroxidation in immortalized neuronal cells exposed to glutamate.
“Indeed, linalool has been shown to counteract the increase of ROS production and mitochondrial Ca2+ levels, to preserve mitochondrial integrity, and to reduce lipid peroxidation in immortalized neuronal cells exposed to glutamate (Sabogal-Guáqueta et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sabogal-Guáqueta et al., 2019
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PremisecitationIn STZ-induced diabetic rats, intragastric geniposide improves insulin resistance and blood glucose, increases IDE, and decreases Aβ1-42.
“In STZ-induced diabetic rats the intragastric administration of geniposide has been demonstrated to improve insulin resistance and blood glucose levels, to increase the expression of IDE and to decrease Aβ1-42 levels (Liu et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2013
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PremisecitationLinalool interferes with glutamatergic transmission, displaying an anticonvulsant effect.
“In line with these results, it has been demonstrated that linalool is able to interfere with the glutamatergic transmission, hence displaying an anticonvulsivant effect (Brum et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brum et al., 2001
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PremisecitationGeniposide acts as GLP-1 receptor agonist and triggers neuroprotective mechanisms including insulin secretion, increased cAMP, and IDE gene expression.
“the ability of geniposide to act as an agonist of the GLP-1 receptor (GLP-1R) and to trigger different neuroprotective mechanisms upon GLP-1R activation, including the induction of insulin secretion, the increase of intracellular cyclic Adenosine Monophosphate (cAMP) levels and the activation of IDE gene expression (Liu et al., 2006; Liu et al., 2009; Liu et al., 2012; Yin et al., 2012; Li et al.,”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Liu et al., 2006
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- cites Liu et al., 2009
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- cites Liu et al., 2012
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PremisecitationGenipin reduces Tau phosphorylation and fibrillation in Tau-overexpressing cells.
“Moreover, it has recently been reported that genipin reduces Tau phosphorylation and fibrillation in Tau-overexpressing cells and decreases the Aβ generation in neuronal cells overexpressing the Swedish mutant APP, by inhibiting BACE-1 expression (Li F et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li F et al., 2021
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PremisecitationGeniposide protects primary hippocampal neurons from Aβ1-42 toxicity by improving mitochondrial axonal trafficking and function and ameliorating synaptic damage.
“geniposide protects primary hippocampal neurons from the Aβ1-42 toxicity by improving mitochondrial axonal trafficking and function and ameliorating synaptic damage (Li et al., 2014; Sun et al., 2014; Zhao et al., 2016; Zhang et al., 2017)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Li et al., 2014
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- cites Sun et al., 2014
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- cites Zhao et al., 2016
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PremisecitationIn mice injected with D-galactose and Aβ, catalpol inhibits oxidative stress and reduces Aβ levels by regulating SOD, GPx, and increasing IDE expression.
“In mice injected with D-galactose and Aβ, the treatment with catalpol is able to inhibit oxidative stress and to reduce Aβ levels by regulating the activity of SOD, GPx and by increasing the expression of IDE, which is involved in the Aβ degradation (Huang et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 2016
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PremisecitationCatalpol is protective against oxidative stress and mitochondrial dysfunction induced by neurotoxins including rotenone, MPP(+), and D-galactose by increasing antioxidant factors, preventing complex I activity reduction, and counteracting lipid peroxidation.
“Many reports have demonstrated that catalpol is protective against the oxidative stress and mitochondrial dysfunction induced by several neurotoxins including rotenone, MPP(+) and D-galactose, by increasing the activity of antioxidant factors, preventing the complex I activity reduction, and counteracting the lipid peroxidation (Mao et al., 2007; Tian et al., 2007; Zhang et al., 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Mao et al., 2007
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- cites Tian et al., 2007
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- cites Zhang et al., 2007
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PremisecitationICV geniposide in STZ-treated rats improves learning and memory deficits, attenuates Tau hyperphosphorylation, and prevents subcellular and synaptic abnormalities by reducing GSK-3 activity.
“the intracerebroventricular (ICV) injection of geniposide in STZ-treated rats was able to improve learning and memory deficits, attenuate Tau hyperphosphorylation and prevent subcellular and synaptic abnormalities by reducing the activity of GSK-3 enzyme (Gao et al., 2014)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gao et al., 2014
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PremisecitationGenipin possesses anti-inflammatory, anti-diabetic, and anti-depressive pharmacological properties.
“the aglycone of geniposide, genipin, which can be produced through the metabolism of geniposide by intestinal microflora enzymes, has recently been reported to possess several pharmacological properties, such as anti-inflammatory, anti-diabetic and anti-depressive effects (Li et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Li et al., 2016
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PremisecitationCatalpol protects neuronal and glial cells from Aβ1-42 toxicity by preventing astrocytic and microglial activation, release of pro-inflammatory factors (ROS, NO, TNF-α), and attenuating mitochondrial-dependent neuronal apoptosis.
“Catalpol has also been reported to protect neuronal and glial cells by Aβ1-42 toxicity by preventing astrocytic and microglial activation and the release of pro-inflammatory factors such as ROS, NO and TNF-α, and by attenuating the mitochondrial-dependent neuronal apoptosis (Jiang et al., 2008; Liang et al., 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Jiang et al., 2008
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- cites Liang et al., 2009
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PremisecitationIn mice intraperitoneally injected with D-galactose to reproduce senescence, catalpol improves cholinergic function, reduces inflammatory cytokine levels, prevents mitochondrial dysfunction, and improves learning and memory deficits.
“In particular, in mice intraperitoneally injected with D-galactose to reproduce senescence, catalpol is able to improve cholinergic function, reduce inflammatory cytokines levels, prevent mitochondrial dysfunction, and improve learning and memory deficits.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Zhang et al., 2007
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- cites Zhang X. et al., 2008
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- cites Zhang X. L. et al., 2008
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PremisecitationIn STZ-induced diabetic rats, limonene exerts an anti-hyperglycemic effect, increases the activity of antioxidant enzymes SOD and GSH, and reduces lipid peroxidation.
“In STZ-induced diabetic rats it exerts an anti-hyperglicemic effect, increases the activity of antioxidant enzymes such as SOD and GSH, and reduces the levels of lipid peroxidation, hence displaying a therapeutic potential in preventing diabetes complications (Murali et al., 2013; Bacanli et al., 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Murali et al., 2013
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- cites Bacanli et al., 2017
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLimonene displays efficacy in preventing or alleviating metabolic disorders in HFD-fed mice.
“Interestingly, limonene also displays an efficacy in preventing or alleviating metabolic disorders in HFD-fed mice (Jing et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jing et al., 2013
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Premisenone givenPhytochemicals have the ability to modulate Aβ aggregation and interfere with the amyloid cascade.
“More recently, their ability to modulate the Aβ aggregation and to interfere with the amyloid cascade has also been demonstrated.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationLimonene induces a significant decrease in the number of activated glial cells and in the expression of NO, exerting an anti-inflammatory effect.
“Moreover, limonene induces a significant decrease in the number of activated glial cells and in the expression of NO, thus also proving to exert an anti-inflammatory effect (Shin et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shin et al., 2020
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PremisecitationIntraperitoneal administration of linalool counteracts Aβ-induced hippocampal injury and ameliorates cognitive deficits in Aβ-treated mice.
“Interestingly, the intraperitoneal administration of linalool counteracts the Aβ-induced hippocampal injury and ameliorates cognitive deficits in Aβ-treated mice.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xu et al., 2017
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Classified as probably not a substantial claim. May combine two claims.
Interpretationnone givenThe identification of the exact mechanism of action and therapeutic target is of crucial importance for accurate selection of participants, which may affect the success of a clinical trial.
“Indeed, the identification of the exact mechanism of action and, hence, of a therapeutic target is of crucial importance for an accurate selection of the participants, which in turn may strongly affect the success of a clinical trial.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenThe major pharmacokinetic limitations leading to clinically irrelevant results include poor ability to cross the BBB and rapid metabolism.
“As mentioned above, the major pharmacokinetic limitations leading to clinically irrelevant results include the poor ability to cross the BBB and rapid metabolism.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLinalool attenuates caspase activation, oxidative stress, and the reduction of Nrf2 expression induced by Aβ.
“Specifically, linalool attenuates caspase activation, oxidative stress, and the reduction of Nrf2 expression induced by Aβ (Xu et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xu et al., 2017
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PremisecitationChronic administration of linalool reduces β-amyloidosis, astrogliosis, and microgliosis and improves spatial and learning memory in triple transgenic AD mice (3xTg-AD).
“In addition, the chronic administration of linalool has been reported to reduce β-amyloidosis, astrogliosis and microgliosis and to improve spatial and learning memory in triple transgenic AD mice (3xTg-AD).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sabogal-Guáqueta et al., 2016
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PremisecitationLimonene displays antioxidant, anti-inflammatory, and anti-nociceptive activities.
“Limonene, a monocyclic monoterpene abundantly found in the genus Citrus (Rutaceae), displays several biological properties including antioxidant, anti-inflammatory and anti-nociceptive activities (Roberto et al., 2010; d’Alessio et al., 2013; Piccinelli et al., 2017).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Roberto et al., 2010
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- cites d’Alessio et al., 2013
Not checked in the free run.
- cites Piccinelli et al., 2017
Not checked in the free run.
The authors state this as an assumption.
Multiple etiological factors may converge in a common pathological manifestation in Alzheimer's disease.
“A “multifactorial hypothesis” of AD assumes that multiple etiological factors may converge in a common pathological manifestation (Figure 1).”
The authors state this as an assumption.
Aging constitutes a predominant risk factor for AD.
“According to the assumption that aging constitutes a predominant risk factor for AD”
The paper relies on this without support.
Most Aβ-targeted drugs tested in clinical trials reduced Aβ burden but did not significantly improve cognitive decline.
“although most of the Aβ-targeted drugs tested in clinical trials unveiled promising results in reducing the Aβ burden, they did not prove a significant efficacy against the cognitive decline”
The paper relies on this without support.
Clinical results from human trials of natural compounds in AD have been mostly insufficient or disappointing.
“while there are a massive number of mechanistic studies suggesting the therapeutic potential of natural compounds in AD and other neurodegenerative diseases, clinical results from human trials have been mostly insufficient or disappointing.”
The paper relies on this without support.
Pharmacokinetic properties of natural compounds determine their bioavailability.
“Another crucial issue is represented by the pharmacokinetic properties of natural compounds that determine their bioavailability, an aspect gaining complexity when it comes to evaluating the efficacy of dietary supplementation with polyphenols, in which the overall dietary intake may be critical.”
The paper relies on this without support.
The composition of gut microbiota may strongly influence and even drive the pharmacological effects of polyphenols.
“since the composition of gut microbiota may strongly influence and even drive their pharmacological effects.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Many experimental preclinical pharmacological studies have demonstrated the efficacy of phytochemicals in the management of Alzheimer's disease.
“Many experimental preclinical pharmacological studies have demonstrated the efficacy of phytochemicals in the management of AD”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [77]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Geniposide is said to suppress mitochondrial function while the cited study says it reduces dysfunction
MinorThe text describes suppression of mitochondrial function as part of geniposide's benefit in APP/PS1 mice. The cited study's title instead says geniposide attenuates mitochondrial dysfunction in those mice.
“In APP/PS1 transgenic mice, the treatment with geniposide ameliorates memory deficits by significantly suppressing oxidative damage, mitochondrial function, and MAPK signaling overactivation (Lv et al., 2014; Zhao et al., 2017).”
“Lv C. Liu X. Liu H. Chen T. Zhang W. (2014). Geniposide Attenuates Mitochondrial Dysfunction and Memory Deficits in APP/PS1 Transgenic Mice.”
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REVIEW: Curcumin and Alzheimer’s disease
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Neuropathology of Alzheimer's Disease
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- Authors
- Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A.
- Affiliations
- University of Naples Federico II (IT)
- University of Salerno (IT)
- Corresponding author
- Pannaccione, Anna
- ORCID
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2022-05-04
- Volume
- 13
- Pages
- 876614-876614
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC9114803
- OpenAlex
- W4225417704
- Semantic Scholar
- dd02bde7544e59359cf3a78981cfacc73a2fe94a
- Cited by
- 73
- References
- 372
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 16 · 2023: 16 · 2022: 3
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, phytochemicals, polyphenols, monoterpenes, amyloid-beta aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, insulin resistance, multi-target therapy, nanotechnology, pharmacokinetic enhancement, lifestyle intervention
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