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The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that soluble Aβ oligomers, rather than insoluble amyloid plaques, are the primary synaptotoxic agents causing early memory failure in Alzheimer’s disease. It synthesizes cell, animal, and human evidence linking oligomers to synaptic plasticity disruption, synapse loss, tau pathology, insulin resistance, and candidate therapeutic strategies.
Key findings
- Aβ oligomers inhibit long-term potentiation (LTP) within minutes without affecting baseline excitability, and memory loss in APP transgenic mice can be reversed by anti-Aβ antibodies without removing amyloid plaques.
- Oligomers accumulate in AD-affected human brain and in essentially all transgenic AD models examined; synthetic and brain-derived oligomers show biochemical identity, and oligomer size remains debated (dimers–tetramers vs. 12mers/24mers), with SDS-stable 12mers linked to memory failure in one model.
- Oligomers target synapses: >90% co-localization with post-synaptic marker PSD-95; 50–85% of hippocampal neurons bind oligomers while others are spared; binding is associated with tau hyperphosphorylation, insulin receptor redistribution, spine loss, and oxidative stress.
- AD is discussed as a brain-specific form of diabetes (“type 3 diabetes”): Aβ oligomers induce insulin resistance, and intranasal insulin improves cognition in early AD at higher doses, consistent with insulin resistance.
Methods
- Narrative review of the literature, not a primary experimental study; it synthesizes findings from cell biology, animal models, human AD brain/CSF, and human genetics.
- Evidence discussed includes synthetic and brain-derived Aβ oligomers, transgenic mouse/rat/C. elegans/Drosophila models, electrophysiology (LTP/LTD), imaging, biochemical assays, and human clinical/ biomarker studies.
- Main analysis is qualitative synthesis; Tables 2 and 3 summarize synapse-specific and more generalized neuronal effects of Aβ oligomers.
Limitations
- Stated: the pathogenic oligomer size is uncertain; detection is limited by SDS-PAGE/Western blot, antibody choice, heat denaturation, and detergent; not all oligomers are toxic; nomenclature is confusing; why toxic oligomers accumulate in sporadic AD is largely unknown; intracellular vs. extracellular localization is unresolved; PrPC involvement is debated; synthetic oligomers can clump at high concentrations.
- Stated: published studies use different oligomer preparations, concentrations, incubation times, brain regions, and culture maturation stages, complicating comparison.
- Evident: as a narrative review, it lacks a systematic search strategy, formal quality appraisal, or meta-analysis, and presents an author-framed argument favoring the oligomer hypothesis.
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In the paper
“A classic study by Terry, Masliah and colleagues subsequently confirmed that synapse loss is the best pathological correlate of Alzheimer’s dementia (Terry et al., 1991).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Amyloid and nerve cell death are not the primary disease-causing pathologies
What the sources say
- Not checked yetcites Terry et al., 1991 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Amyloid in fact is a poor correlate of disease state in AD models as in humans (Terry et al., 1991),”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Amyloid and nerve cell death are not the primary disease-causing pathologies
What the sources say
- Not checked yetcites Terry et al., 1991 source
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In the paper
“Dot immunoblots of soluble extracts from human brain show major increases in oligomers in AD-affected tissue (Gong et al., 2003; Kayed et al., 2003; Lambert et al., 2001).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Most importantly, these amyloid-free Aβ oligomers were potent CNS neurotoxins.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
What the sources say
- Not checked yetcites Lambert et al., 1998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Its clinical relevance has been established by evidence that equivalent oligomers accumulate in AD-affected human brain and animal AD models.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIn the paper
“Mucke and colleague found that synapse loss does not require the presence of amyloid deposits (Mucke et al., 2000).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Amyloid and nerve cell death are not the primary disease-causing pathologies
What the sources say
- Not checked yetcites Mucke et al., 2000 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Recent findings by Bateman and colleagues show that clearance of Aβ in AD patients is reduced by 30% (Mawuenyega et al., 2010).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Why do toxic oligomers accumulate?
What the sources say
- Not checked yetcites Mawuenyega et al., 2010 source
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In the paper
“Recent evidence suggests that insulin resistance, a hallmark of diabetes, develops in Alzheimer’s brains (, 2000; Craft et al., 1999; de la Monte, 2009; Moroz et al., 2008; Pedersen and Flynn, 2004; Razay and Wilcock, 1994; Watson and Craft, 2003).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
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In the paper
“In hippocampal slices, synthetic oligomers cause rapid LTP inhibition (Barghorn et al., 2005; Fa et al., 2010; Jurgensen et al., 2011; Lambert et al., 1998; Nimmrich et al., 2008; Rammes et al., 2011; Wang et al., 2002).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neurological consequences: Oligomers impair synapse plasticity and learning
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“At the cellular level, deficient insulin signaling results in impaired removal of Aβ (Plum et al., 2005) and Aβ oligomers from the extracellular milieu (Zhao et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Why do toxic oligomers accumulate?
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 69
- Probably not a substantial claim. 20
In the paper
“Dodart, Paul and colleagues found that memory loss was reversed in APP tg-mice injected with antibodies against Aβ and that this reversal, moreover, did not require removal of amyloid plaques (Dodart et al., 2002).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Amyloid and nerve cell death are not the primary disease-causing pathologies
What the sources say
- Not checked yetcites Dodart et al., 2002 source
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In the paper
“Investigation into the action of clusterin by Lambert, Klein and colleagues established that, concomitant with inhibition of amyloid formation, clusterin promotes accumulation of soluble Aβ oligomers (Lambert et al., 1998).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
What the sources say
- Not checked yetcites Lambert et al., 1998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“some neuropathologists rejected the hypothesis, emphasizing that a poor correlation exists between plaque load and cognitive function (Terry et al., 1994).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis
What the sources say
- Not checked yetcites Terry et al., 1994
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true.
In the paper
“With chronic exposure, neurons ultimately were killed. Death was selective for subpopulations of vulnerable neurons and was prevented by knockout of Fyn, a protein tyrosine kinase linked to NMDA receptor signaling.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
What the sources say
- Not checked yetcites Lambert et al., 1998 source
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None of the sources cited for this claim have been checked yet.
In the paper
“Based on a central role for impaired signaling, the oligomer hypothesis predicted that early memory loss should be reversible. This prediction was confirmed in the transgenic mouse experiments mentioned above (Dodart et al., 2002; Kotilinek et al., 2002).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“oligomers were found to inhibit functional synaptic plasticity (Lambert et al., 1998). Long-term potentiation (LTP) was inhibited within minutes. This rapid loss of LTP, measured in rat brain slices and in situ in mice, occurred without impact on baseline excitability, indicating impairment of signaling rather than degeneration.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
What the sources say
- Not checked yetcites Lambert et al., 1998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Immunohistochemistry confirms that oligomers associate with neurons, accumulating very early in disease progression (Lacor et al., 2004), in loci distinct from amyloid deposits (Kayed et al., 2003).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“At present it is uncertain whether one class is more germane to pathogenesis than another.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Remarkably, at sub-nanomolar doses, the effect on LTP is reversed, and Aβ markedly enhances LTP. Discovered by Arancio and colleagues in a detailed analysis (Puzzo et al., 2008), enhancement occurs over a narrow range of concentrations and is associated with presynaptic activation of alpha7 nicotinic receptors.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neurological consequences: Oligomers impair synapse plasticity and learning
What the sources say
- Not checked yetcites Puzzo et al., 2008 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“And in fact, not all oligomers are toxic, even those oligomers of a given size. Subtle conformation changes affect toxicity and immunoreactivity (Chromy et al., 2003; Pitt et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Traumatic brain injury also is associated with acutely elevated levels in CSF, with a positive correlation between oligomer levels and severity of sequelae (David Brody, MP Lambert, and WL Klein, unpublished).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Why do toxic oligomers accumulate?
What the sources say
- Not checked yetcites David Brody, MP Lambert, and WL Klein, unpublished
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In FAD, metabolic effects of mutations promote increased levels of total Aβ, or increased Aβ42 to Aβ40 ratio (Borchelt et al., 1996; Citron et al., 1992), conditions that favor oligomerization.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Why do toxic oligomers accumulate?
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“More generalized neuronal impacts of Aβ oligomers (Table 3) include Ca2+ dyshomeostasis, oxidative stress and mitochondrial damage, proteasome inhibition, tau accumulation and hyperphosphorylation, impairment of fast axonal transport, ER stress, inhibition of the proteasome, cell cycle re-entry and, ultimately, cell death.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Synapse-specific and other pathological cellular consequences of ADDL binding to neurons
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The discovery that memory failure in tg mice coincides with the appearance of SDS-stable 12mers is compelling in situ evidence that this species is pathogenic (Lesne et al., 2006).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Clinical relevance: build up of toxic oligomers in AD and AD animal models
What the sources say
- Not checked yetcites Lesne et al., 2006 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Relative levels of Aβ42 to Aβ40 appear to influence the mechanism of oligomerization, with higher levels of Aβ40 in normal individuals likely impeding formation of stable toxic oligomers (Giuffrida et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Why do toxic oligomers accumulate?
What the sources say
- Not checked yetcites Giuffrida et al., 2009 source
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None of the sources cited for this claim have been checked yet.
In the paper
“Tg-mouse AD models manifest a spontaneous age-onset impairment of LTP (Gong et al., 2004) that presumably is linked to impaired performance in memory tests (Arendash et al., 2001).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neurological consequences: Oligomers impair synapse plasticity and learning
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Synapse-specific effects of Aβ oligomers (Table 2) include alterations in neurotransmitter (glutamate/D-serine) levels, down-regulation (due to abnormal trafficking or degradation) of plasticity-related receptors at the plasma membrane, altered plasticity (inhibition of long term potentiation and/or facilitation of long term depression), cytoskeletal abnormalities and synapse loss.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Synapse-specific and other pathological cellular consequences of ADDL binding to neurons
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Memory loss, beginning early in the disease, was attributed to oligomer-induced disruption of synaptic plasticity, with later stages of dementia attributed to oligomer-induced cellular degeneration and death.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Early AD is largely a disease of memory formation, and memory dysfunction is the primary symptom bringing patients to physicians.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Amyloid and nerve cell death are not the primary disease-causing pathologies
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses.”
- Also stated in: § Abstract · plain
“We summarize here why attention has shifted away from amyloid plaques as the toxic agents of AD to the contemporary concept that memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Early AD is largely a disease of memory formation, and memory dysfunction is the primary symptom bringing patients to physicians.
- Rests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.
- Also stated in: § Abstract · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The conclusion that Aβ oligomers can be neurologically significant toxins, possibly the most important ones for AD, is now supported by more than a decade of further investigation, with over 1,000 papers addressing the oligomer hypothesis.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Memory loss is a disruption of synaptic plasticity: the oligomer hypothesis
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it now appears the most pathogenically relevant Aβ-derived toxins are small soluble oligomers, not readily detected.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.
In the paper
“The hypothesis attributed dementia to nerve cell death caused by the toxicity of large insoluble amyloid fibrils.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis
What the sources say
- Not checked yetcites Hardy and Higgins, 1992 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, besides directly affecting memory-related processes, the various impacts of Aβ oligomers on neurons have the potential to account for major facets of AD neuropathology (e.g., tau hyperphosphorylation, oxidative stress, synapse loss), supporting the concept that Aβ oligomers provide a unifying mechanism for initiation of AD pathogenesis.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Synapse-specific and other pathological cellular consequences of ADDL binding to neurons
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Serine phosphorylation precludes tyrosine phosphorylation of IRS-1, blocking downstream insulin signaling.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Physiologically, IRS-1 is phosphorylated at tyrosine residues by the tyrosine kinase activity of the IR, which activates downstream signaling in the insulin pathway (Araki et al., 1994; White, 2003).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“IRs are present in the brain, where they are abundantly distributed in synaptic membranes of the cerebral cortex and hippocampus (Abbott et al., 1999; Havrankova et al., 1981; Marks et al., 1990; Unger and Betz, 1998).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ oligomers induce a striking redistribution of IRs, causing their internalization from dendritic membranes and accumulation in the cell body. This renders neurons insulin resistant (De Felice et al., 2009; De Felice et al., 2008; Zhao et al., 2008).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Brain insulin signaling declines with age (Frolich et al., 1998; , 1999; Hoyer, 1998; Rivera et al., 2005), the primary risk factor for AD.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“an elevated risk for AD also exists in type 2 diabetes patients, who manifest deficient CNS insulin signaling (Matsuzaki et al., 2010; Ott et al., 1999; Toro et al., 2009; Watson and Craft, 2003), likely as a consequence of decreased insulin uptake into the brain following sustained peripheral hyperinsulinemia (Gerozissis et al., 1993; Kaiyala et al., 2000; Schwartz et al., 1990).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Internalization occurs by a mechanism mediated by casein kinase 2 (CK2) and Ca2+/calmodulin-dependent kinase 2 (CaMK II), which also are involved in ADDL-induced internalization of NMDA receptors (De Felice et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
- Not checked yetcites De Felice et al., 2009 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The possible source of extracellular oligomers and how they interact with neurons in human brain are suggested by their peri-somatic localization, observed in early-stage disease (Figure 1, left; (Lacor et al., 2004)).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
What the sources say
- Not checked yetcites Lacor et al., 2004 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, physiological insulin signaling may play an important role in defending neurons against AD, suggesting the loss of CNS insulin signaling in aging and diabetes is a potential risk factor for AD.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“When given to subjects with early AD, intranasal insulin also improves performance (Reger et al., 2008b) but only at higher doses, consistent with expected insulin resistance and suggesting possible involvement of additional mechanisms other than stimulation of plasticity.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
- Not checked yetcites Reger et al., 2008b
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Aβ oligomers induce a marked removal of IRs from synapses, decreasing the responsiveness of nerve cells to insulin.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The insulin-sensitizing drug rosiglitazone, a PPAR-γ agonist, potentiates the ability of insulin to protect synapses against Aβ oligomers, while a cell-permeant inhibitor of the tyrosine kinase activity of the IR abrogates the protection by insulin.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
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In the paper
“insulin itself blocks the pathological binding of Aβ oligomers and the resulting redistribution of IRs and synapse loss (De Felice et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
- Not checked yetcites De Felice et al., 2009 source
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None of the sources cited for this claim have been checked yet.
In the paper
“the ability of antibodies to reverse intracellular tau and synapse pathology (Chauhan et al., 2008; Oddo et al., 2006) and to provide cognitive benefits (Hillen et al., 2010; Takamura et al., 2011).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
What the sources say
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In the paper
“stimulation of insulin signaling also protects against accumulation of hyperphosphorylated tau (Escribano et al., 2010), a pathological hallmark of AD that is induced by Aβ oligomers (De Felice et al., 2008).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
What the sources say
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In the paper
“The mechanism of protection does not involve direct competition between Aβ oligomers and insulin for a common binding site on the neuronal surface. Rather, it consists of an IR signaling-dependent down-regulation of neuronal ADDL binding sites.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Neuronal insulin resistance induced by Aβ oligomers: AD as a novel form of brain-specific diabetes
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In the paper
“Clustering of oligomers at synapses, moreover, shows a cause-and-effect relationship with characteristic Alzheimer neuropathologies. AD type tau hyperphosphorylation (De Felice et al., 2008), redistribution of insulin receptors (De Felice et al., 2009; Zhao et al., 2008), spine loss (Lacor et al., 2007) and oxidative stress (De Felice et al., 2007; Decker et al., 2010a) are manifest exclusively in”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, the peri-somatic distribution in human brain is evident in the complete absence of amyloid plaques, indicating oligomer pathology occurs early in the disease process.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As expected, the pattern of binding depends on cell maturation.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These oligomer-targeted neurons are distributed sparsely, indicating oligomers might originate within the cells they surround (Figure 1, right).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It can be concluded that oligomers are gain-of-function pathogenic ligands that target and disrupt signaling at particular synapses, a specificity that may explain why early AD is a disease of memory.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
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In the paper
“Aβ oligomers bind with nanomolar affinity to cellular prion protein (PrPC) and that anti-PrP antibodies reduce oligomer binding to neurons and rescue synaptic plasticity (Lauren et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites Lauren et al., 2009 source
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In the paper
“Significantly, some neurons are targeted while others are not, establishing clear-cut specificity.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Initiating mechanisms – the targets are synapses
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“EphB2 receptors interact functionally and physically with NMDARs at synapses”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
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In the paper
“Other putative receptors/co-receptors involved in neuronal binding of Aβ oligomers include the p75 neurotrophin receptor (p75NTR) (Knowles et al., 2009), the receptor for advanced glycation end products (RAGE) (Sturchler et al., 2008), nicotinic acetylcholine receptors (Magdesian et al., 2005) and Frizzled (Magdesian et al., 2008).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggest that ADDL binding to synapses may involve the assembly of a multi-protein receptor whose assembly is promoted by NMDARs and likely involves other participants, including PrPC.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations indicate that NMDARs are necessary but not sufficient for ADDL binding”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
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In the paper
“This suggests that initial ADDL binding recruits more PrPC molecules (presumably by exocytosis of vesicles located proximal to the plasma membrane; (Caetano et al., 2011)) to form a higher order complex that may initiate toxic signaling at”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites Caetano et al., 2011 source
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In the paper
“NMDARs co-immunoprecipitate with Aβ oligomers from detergent-extracted oligomer-treated rat synaptosomal membranes, and an N-terminal anti-NR1 antibody markedly reduced oligomer binding to dendrites (De Felice et al., 2007).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites De Felice et al., 2007 source
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In the paper
“NMDAR knock-down also abrogates neuronal oxidative stress induced by Aβ oligomers, which is mediated by aberrant activation of NMDARs (De Felice et al., 2007).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites De Felice et al., 2007 source
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None of the sources cited for this claim have been checked yet.
In the paper
“A second prediction based on altered Arc expression is that oligomers would induce aberrant dendritic spine morphology, and this also has been confirmed in culture and in situ (Lacor et al., 2007; Ma et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Lacor et al., 2007 source
- Not checked yetcites Ma et al., 2009
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although receptors are lost from the surface, total levels are at first unchanged, indicating dysfunctional trafficking”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“What emerges from current evidence is that Aβ oligomers first bind to the neuronal plasma membrane at freely moving receptors, but lateral diffusion leads to interactions between Aβ oligomers and membrane proteins such as mGluR5 that ultimately target Aβ oligomers to synaptic sites.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
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In the paper
“Initially, Aβ oligomers diffused as if bound to an untethered protein. Within minutes, however, movement slowed and oligomers became immobilized, typically at active synapses labeled with FM4-64. The synaptic trapping of oligomers was accompanied by co-clustering and immobilization of mGluR5 metabotropic glutamate receptors.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites Renner et al., 2010 source
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None of the sources cited for this claim have been checked yet.
In the paper
“Because Arc is an actin binding protein, its aberrant expression was predicted to disrupt receptor trafficking (Lacor et al., 2004), which could consequently disrupt plasticity (Gong et al., 2003).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“explaining the finding that knocking-down these proteins or adding antibodies against their extracellular domains blocks the accumulation of ADDL clusters (“hotspots”) at synapses (De Felice et al., 2007; Decker et al., 2010a; Lauren et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Within minutes of exposure to oligomers, neurons show a localized over-expression of Arc, which later spreads ectopically throughout the dendrite.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Arc is an immediate early gene product that is translated from mRNA in dendritic spines (Bramham, 2008).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Bramham, 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The mechanism of oligomer synapto-toxicity appears to be tied closely to accumulation of excessive levels of Ca++ (Marx, 2007), consistent with involvement of NMDA and mGluR5 receptors.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Marx, 2007 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interaction with Aβ oligomers could potentially dysregulate such signaling pathways, resulting in neurotoxicity.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
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None of the sources cited for this claim have been checked yet.
In the paper
“PrPC has been proposed to act as a cell-surface platform that orchestrates several physiological signaling pathways at the neuronal plasma membrane (for reviews, see (Linden et al., 2008; Martins et al., 2010)).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > How spines are targeted by Aβ oligomers – receptors, co-receptors, scaffolds and toxic clusters
What the sources say
- Not checked yetcites Linden et al., 2008 source
- Not checked yetcites Martins et al., 2010
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The consequent chronic mGluR5 activity would keep FMRP dephosphorylated and eliminate the ability of FMRP to repress mRNA translation.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
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In the paper
“Such aberrant spines also are seen in traumatic brain injury and prionoses (Fiala et al., 2002).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Fiala et al., 2002 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Fragile X also leads to hyperactivity in the protein phosphatase PP2a (Kim et al., 2008) which inactivates MAPK, an enzyme with impaired activity in oligomer-exposed neurons (Tong et al., 2001).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hyperactivity of mGluR5 receptors caused by oligomers is due to a clustering mechanism, as described earlier, and this receptor state hypothetically could be insensitive to negative feedback by FMRP.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Spines after short-term exposure to oligomers are long and spindly, resembling immature spines that express low levels of AMPA-Rs, as found early in development.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In the absence of FMRP, mGluR5 is hyperactive, with the consequences detailed above, and mGluR5 antagonists have been suggested as an approach to Fragile X treatment.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This mechanism is in many respects analogous to the clustering of receptors at immunological synapses during T cell activation (Douglass and Vale, 2005), with the fundamental difference that oligomer-induced clustering is toxic.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Douglass and Vale, 2005
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Its control of Arc is a prime example (Iacoangeli et al., 2008).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
What the sources say
- Not checked yetcites Iacoangeli et al., 2008 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Eventually, spines deteriorate and synapses are lost, consistent with low levels of Arc found in mature tg-mice (Chin et al., 2005).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
- Not checked yetcites Chin et al., 2005 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Additional synaptic pathologies instigated by oligomers also are present in Fragile X, including aberrant spine morphology, loss of NMDA and AMPA receptors, and elevated LTD (Bear et al., 2004).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
What the sources say
- Not checked yetcites Bear et al., 2004 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Fragile X is a developmental disorder caused by inability to express the regulatory protein FMRP.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Another actin binding protein found in spines, drebrin, also becomes greatly diminished in culture (Lacor et al., 2007) and in tg-mice (Calon et al., 2004).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Clustering can be elicited by mGluR5 antibodies, and antibody-induced clustering mimics the effects of oligomers in causing elevated Ca++ and synapse deterioration.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Oligomer-induced Ca++ elevation: Consequences and a novel triggering mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“there is also reason to believe that non-pharmacological approaches based on these novel findings might be beneficial to ameliorate AD symptoms (Schaeffer et al., 2009).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
What the sources say
- Not checked yetcites Schaeffer et al., 2009 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Coupled with the potential of dendrites for activity-stimulated exocytosis (Kennedy et al., 2010), such a phenomenon could account for the “perineuronal deposits” of oligomers seen in Figure 1 (Lacor et al., 2004).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, exercise and a balanced diet might have positive effects on both peripheral and brain insulin signaling.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One of the implications of this finding is that D1/D5 receptors may constitute a target for the development of novel approaches to combat synapse failure in AD.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In particular, the discovery that insulin resistance plays an important role in the pathogenesis of AD suggests that strategies aimed to bolster brain insulin signaling might be beneficial in preventing synapse failure and neuronal damage in AD.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“dopaminergic neurotransmission, centrally implicated in the brain reward system and known to decline with aging (De Keyser et al., 1990), plays important roles in non-pharmacological strategies aimed to improve age-related cognitive decline, such as environmental enrichment and physical exercise (van Praag et al., 2000).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
What the sources say
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Oligomer-induced hyperactivity of mGluR5 in Alzheimer’s disease would thus promote production of even more Aβ and oligomers.”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Comparison with another disorder of learning and memory: AD and Fragile X Syndrome show striking similarities
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“a connection has recently been established between dopaminergic signaling and AD, with demonstration that selective activation of D1/D5 dopamine receptors prevents pathological changes in synapse composition and function (including inhibition of LTP) induced by Aβ oligomers (Jurgensen et al., 2011).”
§ The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas > The original amyloid cascade hypothesis > Promise of therapeutics
What the sources say
- Not checked yetcites Jurgensen et al., 2011 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Early AD is largely a disease of memory formation, and memory dysfunction is the primary symptom bringing patients to physicians.
“the symptom that first brings patients to a physician is a troubling inability to form new memories, and early AD is largely regarded as a disease of memory formation.”
The paper relies on this without support.
AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.
“This article reviews progress in the search for primary AD-causing toxins.”
“If we could regard AD as having a single disease-initiating cytotoxin (albeit one likely elicited by multiple factors), its action minimally must provide a basis for memory dysfunction.”
The authors state this as an assumption.
Aβ oligomers act from the extracellular milieu.
“A premise for investigating the effects of exogenous oligomers on memory and neuropathology is that oligomers presumably act from the extracellular milieu.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“Thus, the production of Aβ is a complex process and accumulating evidence indicates that soluble Aβ oligomers, not Aβ plaques alone, are the disease-causing species that induce substantial neurotoxicity including synaptic dysfunction and behavioral impairment [see review in Ref. (138)].”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [138]
In the citing paper
“In vivo and in vitro studies support a direct relationship between OS and synaptic dysfunction in AD [18,86,87,88,89,90].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [88]
Citations
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2 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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RetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Items 201–300 of 442
Sebollela, A. S., Cline, E. N., Popova, I. A., Luo, K., Sun, X., Ahn, J., Barcelos, M. A., Bezerra, V. N., Silva, N. M. L. E., Patel, J., et al. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14118 · Cited by 38
“…934--947 Evidence obtained during the past two decades implicates the accumulation of soluble Ab oligomers (AbOs) in the brain, rather than fibrillar Ab deposits in plaques, as the primary synaptotoxic form of Ab (Ferreira and Klein 2011; Hayden and Teplow 2013; Klein 2013; Selkoe and Hardy 2016).”
Self-citationYang, W., Zhang, J., Shi, L., Ji, S., Yang, X., Zhai, W., Zong, H.-F., & Qian, Y. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.12.011 · Cited by 35
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“various processes that underlie AD pathogenesis including synaptic dysfunction and Ca2+ deregulation (Ferreira and Klein, 2011; Walsh and Selkoe, 2007).”
BackgroundShastri, D., Raj, V., & Lee, S.-K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102379 · Cited by 34
Takach, O. P., Gill, T. B., & Silverman, M. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.11.018 · Cited by 34
“Amyloid-b oligomers (AbOs), a neurotoxin implicated in AD, induce a variety of cellular insults, including synaptic failure, dysregulation of intracellular signaling cascades, hyperphosphorylation of tau, and disruption of fast axonal transport (FAT) (Ferreira and Klein, 2011).”
Devi, L., & Ohno, M. (2016) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2016.03.002 · Cited by 34
“Since soluble Aβ oligomers represent a critical mediator of memory failure in AD (Ferreira and Klein, 2011; Haass and Selkoe, 2007; Zahs and Ashe, 2013) and the major Aβ in 5XFAD mice is Aβ42 that is more toxic or prone to aggregation than Aβ40 (Oakley et al., 2006; Ohno et al., 2006), we tested…”
Royal jelly peptides: potential inhibitors of β-secretase in N2a/APP695swe cells
Zhang, X., Yu, Y., Sun, P., Fan, Z., Zhang, W., & Feng, C. (2019) · Scientific Reports · doi:10.1038/s41598-018-35801-w · Cited by 34
Salimi, A., Li, H., Shi, H., & Lee, J. Y. (2019) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2019.02.007 · Cited by 34
Graphene quantum dots obstruct the membrane axis of Alzheimer's amyloid beta
Tang, H., Li, Y., Käkinen, A., Andrikopoulos, N., Sun, Y., Kwak, E., Davis, T. P., Ding, F., & Ke, P. C. (2021) · Physical Chemistry Chemical Physics · doi:10.1039/d1cp04246g · Cited by 36
Rashno, M., Gholipour, P., Salehi, I., Komaki, A., Rashidi, K., Khoshnam, S. E., & Ghaderi, S. (2022) · Journal of Functional Foods · doi:10.1016/j.jff.2022.105117 · Cited by 36
Taniguchi, K., Yamamoto, F., Arai, T., Yang, J., Sakai, Y., Itoh, M., Mamada, N., Sekiguchi, M., Yamada, D., Saitoh, A., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190098 · Cited by 34
Rammes, G., Mattusch, C., Wulff, M., Seeser, F., Kreuzer, M., Zhu, K., Deussing, J. M., Herms, J. W., & Parsons, C. G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.02.003 · Cited by 37
“…than the insoluble deposits, are primarily responsible for both the neurodegeneration and especially the impairment of synaptic function in AD (Barghorn et al., 2005; Demuro et al., 2010; Ferreira et al., 2007, 2011; Ferreira and Klein, 2011; Lacor et al., 2007; Wilcox et al., 2011; Xia, 2010).”
Sellés, M. C., Fortuna, J. T. S., Cercato, M. C., Santos, L. E., Domett, L., Bitencourt, A. L. B., Carraro, M. F., de Souza, A. S., Janíčková, H., Azevedo, C. V., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.11.002 · Cited by 35
Self-citationAmyloidβ Peptides in interaction with raft-mime model membranes: a neutron reflectivity insight
Rondelli, V., Brocca, P., Motta, S., Messa, M., Colombo, L., Salmona, M., Fragneto, G., Cantú, L., & Favero, E. D. (2016) · Scientific Reports · doi:10.1038/srep20997 · Cited by 33
“We focus on two conditions: 1) when the Aβ(1-42) reaches the raft-mime surface already in the membrane-active structured-oligomer state and 2) when early, unstructured Aβ(1-42) forms are administered and peptide oligomerization possibly takes place at the membrane.”
BackgroundMethodInfluentialMendes, N. D., Fernandes, A., de Almeida, G. M., Santos, L. E., Sellés, M. C., Silva, N. M. L. E., Machado, C. D. M., Horta‐Júnior, J. D. A. C., Louzada, P. R., Felice, F. G. D., et al. (2018) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2018.05.021 · Cited by 35
Self-citationRammes, G., Seeser, F., Mattusch, K., Zhu, K., Haas, L. T., Kummer, M. P., Heneka, M. T., Herms, J. W., & Parsons, C. G. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.07.021 · Cited by 30
“…than the insoluble deposits, are primarily responsible for both the neurodegeneration and especially the impairment of synaptic function in AD (Barghorn et al., 2005; Demuro et al., 2010; Ferreira et al., 2007, 2011; Ferreira and Klein, 2011; Lacor et al., 2007; Wilcox et al., 2011; Xia, 2010).”
Lackie, R. E., Marques-Lopes, J., Ostapchenko, V. G., Good, S. C., Choy, W., van Oosten‐Hawle, P., Pasternak, S., Prado, V. F., & Prado, M. A. M. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01013-5 · Cited by 32
Parsons, C. G., Ruitenberg, M., Freitag, C. E., Sroka, K., Russ, H., & Rammes, G. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.12.038 · Cited by 31
Králová, K., Fousková, M., Habartová, L., Fišar, Z., Jirák, R., Raboch, J., & Setnička, V. (2019) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2019.04.002 · Cited by 31
Family C G-Protein-Coupled Receptors in Alzheimer’s Disease and Therapeutic Implications
Prà, I. D., Armato, U., & Chiarini, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01282 · Cited by 31
“However, it is still hard to diagnose the earliest asymptomatic stage of AD because specific biomarkers are few and the highly neurotoxic, synapsedestroying sAβ42-os are hardly detectable when senile plaques and NFTs are still absent (Selkoe, 2008a; Selkoe, 2008b; Ferreira and Klein, 2011; Klein, 2013; Dal Prà et al.,…”
BackgroundKommaddi, R. P., Gowaikar, R., Haseena, P. A., Diwakar, L., Singh, K. P., & Mondal, A. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105619 · Cited by 29
Aβ pathology downregulates brain mGluR5 density in a mouse model of Alzheimer
Lee, M., Lee, H., Park, I. S., Park, J. A., Kwon, Y., Ryu, Y. H., Kim, C. H., Kang, J. H., Hyun, I. Y., Lee, K. C., et al. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.02.003 · Cited by 30
“Dysregulation of mGluR5 by Abo synaptic toxicity is known to be related with the early symptoms of cognitive dysfunction in AD (Ferreira and Klein, 2011; Revett et al., 2013).”
A metabolic perspective of late onset Alzheimer’s disease
Ettcheto, M., Cano, A. C., Busquets, O., Manzine, P. R., Sánchez‐López, E., Castro-Torres, R. D., Beas‐Zárate, C., Verdaguer, E., García, M. L., Olloquequi, J., et al. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104255 · Cited by 31
Viola, K. L., Bicca, M. A., Bebenek, A. M., Kranz, D. L., Nandwana, V., Waters, E. A., Haney, C. R., Lee, M. Y., Gupta, A., Brahmbhatt, Z., et al. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.768646 · Cited by 29
Self-citationDorner‐Ciossek, C., Kroker, K. S., & Rosenbrock, H. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-58811-7_9 · Cited by 29
Targeting Pathological Amyloid Aggregates with Conformation-Sensitive Antibodies
Bigi, A., Loffredo, G., Cascella, R., & Cecchi, C. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666201109093848 · Cited by 29
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Past to Future: What Animal Models Have Taught Us About Alzheimer’s Disease
Martini, A. C., Forner, S., Trujillo‐Estrada, L., Baglietto‐Vargas, D., & LaFerla, F. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179917 · Cited by 27
Alzheimer Disease Clinical Trials Targeting Amyloid
Reiss, A. B., Montufar, N., DeLeon, J. R., Pinkhasov, A., Gomolin, I. H., Glass, A. D., Arain, H. A., & Stecker, M. M. (2021) · The Neurologist · doi:10.1097/nrl.0000000000000320 · Cited by 27
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Pharmacological Strategies to Improve Dendritic Spines in Alzheimer’s Disease
Ettcheto, M., Busquets, O., Cano, A. C., Sánchez‐López, E., Manzine, P. R., Espinosa-Jiménez, T., Verdaguer, E., Sureda, F. X., Olloquequi, J., Castro-Torres, R. D., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-201106 · Cited by 25
SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy
Yin, X., Li, Y., Fan, X., Huang, F., Qiu, Y., Zhao, C., Zhou, Z., Gu, Q., Xia, L., Bao, J., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01689-2 · Cited by 28
Devi, L., & Ohno, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.037 · Cited by 28
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript synaptic and memory failure in AD (Haass and Selkoe, 2007, Ferreira and Klein, 2011, Zahs and Ashe, 2013).”
BackgroundWilliams, S. M., Schulz, P., Rosenberry, T. L., Caselli, R. J., & Sierks, M. R. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161116 · Cited by 24
“Alzheimer’s disease (AD) is an age-related neu29 rodegenerative disorder characteristically leading to 30 progressive memory loss which affects the perfor31 mance of normal everyday tasks, ultimately requiring 32 24-hour care [1, 2].”
BackgroundAnalysis of Physicochemical Interaction of Aβ40 with a GM1 Ganglioside-Containing Lipid Membrane
Vahed, M., Neya, S., Matsuzaki, K., & Hoshino, T. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.8b00139 · Cited by 26
Hsueh, Y. (2012) · Journal of Biomedical Science · doi:10.1186/1423-0127-19-33 · Cited by 25
Liu, B., Li, X., Liu, Z., He, B., Xu, H., Cao, J., Zeng, F., Feng, H., Ren, Y., Li, H., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00252 · Cited by 27
Fonseca‐Gomes, J., Costa-Coelho, T., Ferreira-Manso, M., Inteiro-Oliveira, S., Vaz, S. H., Alemãn-Serrano, N., Atalaia-Barbacena, H., Ribeiro‐Rodrigues, L., Ramalho, R. M., Pinto, R. R., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.08.022 · Cited by 27
Intranasal Paclitaxel Alters Alzheimer’s Disease Phenotypic Features in 3xTg-AD Mice
Cross, D. J., Huber, B. R., Silverman, M. A., Cline, M. M., Gill, T. B., Cross, C. G., Cook, D. G., & Minoshima, S. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210109 · Cited by 25
“Although they may not be identical to natural oligomers, synthetic A (cid:2) Os are a tractable tool for investigating mechanisms of AD pathogenesis [41].”
DiChiara, T., DiNunno, N., Clark, J. R., Bu, R. L., Cline, E. N., Rollins, M. G., Gong, Y., Brody, D. L., Sligar, S. G., Velasco, P. T., et al. (2017) · PubMed · Cited by 25
Self-citationHerline, K., Prelli, F., Mehta, P. D., MacMurray, C., Goñi, F., & Wısnıewskı, T. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0384-9 · Cited by 24
Ramamoorthy, K., Yoshimura, R. F., Al-Juburi, S., Anandam, K. Y., Kapadia, R., Alachkar, A., Abbott, G. W., & Said, H. M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105799 · Cited by 25
“Neuroinflammation occurs over the degenerative course of the disease and leads to progressive synapse loss and degeneration of specific neuronal populations (Baleriola et al., 2014; Monsonego et al., 2001; Selkoe, 2002; Ferreira and Klein, 2011; Ferreira et al., 2014; Lue et al., 2001).”
BackgroundThe Role of Oxytocin in Alzheimer’s Disease and Its Relationship with Social Interaction
Takahashi, J., Yamada, D., Nagano, W., & Saitoh, A. (2023) · Cells · doi:10.3390/cells12202426 · Cited by 25
“However, recent studies have shown that the A β oligomers are more neurotoxic than the A β fibrils [5].”
BackgroundKroker, K. S., Moreth, J., Kußmaul, L., Rast, G. F., & Rosenbrock, H. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.04.006 · Cited by 24
APP Causes Hyperexcitability in Fragile X Mice
Westmark, C. J., Chuang, S.-C., Hays, S. A., Filon, M. J., Ray, B. C., Westmark, P. R., Gibson, J. R., Huber, K. M., & Wong, R. K. S. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00147 · Cited by 24
“APP and metabolites play key roles in regulating synaptic activity with both Aβ and sAPPα implicated in positive feedback loops that facilitate mGluR5 signaling (Casley et al., 2009; Renner et al., 2010; Ferreira and Klein, 2011; Westmark et al., 2011, 2013b; Pasciuto et al., 2015).”
BackgroundProbing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers
Fawver, J. N., Duong, K. T., Wise-Scira, O., Chapa, R. P., Schall, H. E., Coskuner‐Weber, O., Zhu, X., Colom, L. V., & Murray, I. V. J. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120880 · Cited by 24
Fitzgerald, G. S., Chuchta, T. G., & McNay, E. C. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14160 · Cited by 22
Lignans from a wild vegetable (Patrinina villosa) able to combat Alzheimer’s disease
Bai, M., Yao, G., Liu, S.-F., et al. (2016) · Journal of Functional Foods · doi:10.1016/j.jff.2016.10.024 · Cited by 23
The Effects of N-terminal Mutations on β-amyloid Peptide Aggregation and Toxicity
Foroutanpay, B. V., Kumar, J., Kang, S., Danaei, N., Westaway, D. A., Sim, V. L., & Kar, S. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.03.014 · Cited by 24
Ge, X., Wang, Y., Yu, S., Cao, X., Chen, Y., Cheng, Q., & Ding, F. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.716177 · Cited by 22
“Toxic AβOs accumulate in the brain, leading to synapse failure, memory loss, and depressive-like behavior, which is closely related to the activation of inflammatory pathways (West et al., 1994; Ferreira and Klein, 2011; Viola and Klein, 2015; Ledo et al., 2016).”
BackgroundIn vitro and in vivo models for anti-amyloidosis nanomedicines
Käkinen, A., Javed, I., Davis, T. P., & Ke, P. C. (2021) · Nanoscale Horizons · doi:10.1039/d0nh00548g · Cited by 23
Iqbal, S., Malik, M. Z., & Pal, D. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e08502 · Cited by 22
“The neuro fi brillary tangles formed by hyperphosphorylated Tau protein lose their physiological role in promoting microtubule stability in neurons [3, 4].”
BackgroundEttcheto, M., Petrov, D., Pedrós, I., de Lemos, L., Pallàs, M., Alegret, M., Laguna, J. C., Folch, J., & Camins, A. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.03.010 · Cited by 22
“Until recently, it waswidely accepted that an increase in cerebral soluble β-amyloid levels in general and soluble β1–42 in particular, is the principal contributor to AD progression (Hardy and Allsop, 1991; Swerdlow et al., 2010; Beauchet et al., 2014; Ferreira and Klein, 2011).”
BackgroundAffuso, F., Micillo, F., & Fazio, S. (2024) · Biomedicines · doi:10.3390/biomedicines12081888 · Cited by 25
“This determines a reduced response to insulin, as documented in neurons cultured in presence of A β oligomers [48,49] (Figure 2).”
BackgroundKishimoto, Y., Higashihara, E., Fukuta, A., Nagao, A., & Kirino, Y. (2012) · Brain Research · doi:10.1016/j.brainres.2012.10.066 · Cited by 21
“…the cognitive impairments in the 5-month-old Tg2576 mice support the hypothesis that the early synapse loss and cognitive impairments that are associated with AD are correlated with soluble Ab oligomer levels rather than fibrillar amyloid deposits (Desbene et al., 2012; Ferreira and Klein, 2011).”
BackgroundNery, L. R., Silva, N. E., Fonseca, R. S., & Vianna, M. R. M. R. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2327-4 · Cited by 25
Borreca, A., Latina, V., Corsetti, V., Middei, S., Piccinin, S., Valle, F. D., Bussani, R., Ammassari‐Teule, M., Nisticò, R., Calissano, P., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0974-3 · Cited by 18
Amyloid beta-protein and lipid rafts focused on biogenesis and catabolism
Araki, W. (2015) · Frontiers in bioscience · doi:10.2741/4311 · Cited by 21
“In particular, numerous reports have indicated that soluble Ab oligomers in the brain are the key pathogenic structures in AD (63,64).”
BackgroundExploring the New Horizon of AdipoQ in Obesity-Related Alzheimer’s Dementia
Uddin, M. S., Rahman, M. M., Sufian, M. A., Jeandet, P., Ashraf, G. M., Bin-Jumah, M. N., Mousa, S. A., Abdel‐Daim, M. M., Akhtar, M. F., Saleem, A., et al. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.567678 · Cited by 21
“Exciting data suggest that Aβ oligomers serve as neurotoxins that accumulate in the brain of AD patients leading to synaptic dysfunction and impaired synaptic plasticity as well as triggering synapse injury (Lambert et al., 1998; Ferreira and Klein, 2011; Forny-Germano et al., 2014).”
BackgroundNameni, G., Hajiluian, G., Shahabi, P., Farhangi, M. A., Abbasi, M. M., Hemmati, M.-R., & Vatandoust, S. M. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0864-y · Cited by 20
“Additionally, overexpression of proinflammatory cytokines like interleukin (IL)-6, TNF-α, and IL-1β in obesity, which can cross the BBB and join the microglial activation-mediated neuroinflammatory pathways, contributes to neuronal death (Ferreira and Klein 2011; Ferreira et al. 2007).”
BackgroundTau Spread, Apolipoprotein E, Inflammation, and More
Gonzalez, B. L., Abud, E. M., Abud, A. M., Poon, W. W., & Gylys, K. H. (2017) · Neurologic Clinics · doi:10.1016/j.ncl.2017.01.001 · Cited by 20
Pathogenic Effects of Impaired Retrieval between the Endoplasmic Reticulum and Golgi Complex
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“In Alzheimer’s disease, intracellular neurofibrillary tangles consisting of insoluble tau protein, as well as extracellular senile plaques composed of amyloid-β, are observed [63].”
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“AβOs are notorious and potent synaptotoxins that obstruct synaptic plasticity [105].”
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“AβOs exist in AD brain tissues [8,9], are tightly linked to Aβ plaque pathology in AD brains [13], and may be sequestered into senile plaques [14].”
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“…that amyloid-β oligomers (A β Os), soluble neu-rotoxins that accumulate in the AD brain and trigger synapse failure and cognitive impairment, 8,9 promote aberrant phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2 α ), 8,10 leading to…”
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“Soluble Aβ oligomers have been suggested to be more toxic than Aβ senile plaques [63], and several findings support this [64,65].”
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“Neuronal degeneration begins with early neuronal dysfunction mediated by AβOs, which disrupts the synapse and inhibits long-term potentiation (LTP; Lambert et al., 1998; Selkoe, 2008; Ferreira and Klein, 2011; Tu et al., 2014).”
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“Indeed, abnormalities in insulin and IGF1 signaling pathway have been observed in brains with AD (Steen et al., 2005; Talbot et al., 2012), and are linked to neuronal dysfunction in AD (Ferreira et al., 2011; Selles et al., 2020).”
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“Growing evidence exists for Aβ oligomers as the disease causing agent of AD, responsible for progression of the disease and cognitive decline (Ferreira and Klein 2011; Ferreira et al. 2015).”
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“The hypothesis that Aβ neurotoxicity is explained by the neuronal impact of soluble AβOs has gained considerable support in the past two decades (Ferreira and Klein, 2011; Cline et al., 2018).”
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“neurofibrillary tangles which are the dominant features of AD [2, 3, 4, 5].”
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“…brain inflammation, impaired axonal transport, increased formation of neuronal reactive oxygen species, increased tau phosphorylation and formation of neurofibrillary tangles, and mitochondrial damage are all characteristic of AD pathologies (Ferreira & Klein, 2011; Young-Pearse et al., 2023).”
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“Early in the disease, toxic soluble amyloid-b (Ab) oligomers disrupt the structure and function of neuronal synapses (Ferreira and Klein, 2011; Lacor et al., 2007).”
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“Numerous studies have investigated how Aβ and tau impact the hippocampus (e.g., Ferreira and Klein 2011), known to be fundamentally involved in acquisition, consolidation, and recollection of new episodic memories (Frozza, Lourenco, and De Felice 2018).”
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“Since synaptic plasticity is believed to have the primary responsibility for learning and memory, its loss can cause cognitive deficiency (Ferreira & Klein, 2011; Gouras, Tampellini, Takahashi, & Capetillo-Zarate, 2010; Klein, 2013; Pham, Chim, Goulding, & Nowick, 2013; Rangachari et al., 2007).”
Background
Metadata
- Authors
- Ferreira, S. T., & Klein, W. L.
- Affiliations
- Universidade Federal do Rio de Janeiro (BR)
- Northwestern University (US)
- Corresponding author
- Klein, William L.
- Venue
- Neurobiology of Learning and Memory
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 96
- Issue
- 4
- Pages
- 529-543
- ISSN
- 1074-7427 (ISSN-L)
- PMC
- PMC4390395
- OpenAlex
- W2051268743
- Cited by
- 442
- References
- 286
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 22 · 2023: 24 · 2022: 37 · 2021: 28 · 2020: 35 · 2019: 23 · 2018: 44 · 2017: 41 · 2016: 33 · 2015: 35 · 2014: 38 · 2013: 24 · 2012: 26
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Learning and Memory (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG022547, R01AG029460, R01AG018877)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, memory loss, amyloid plaques, pathogenesis, diabetes mellitus, fragile X syndrome, animal models of Alzheimer's disease, Alzheimer's disease treatment
- MeSH terms
- Alzheimer Disease, Brain, Humans, Memory Disorders, Neurons, Synapses, Amyloid beta-Peptides, Plaque, Amyloid
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