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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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Items 101–200 of 442
Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice
Buskila, Y., Crowe, S. E., & Ellis-Davies, G. C. R. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.016 · Cited by 77
“P A A uthor M anuscript Discussion It is widely thought that subtle effects of amyloid oligomers on synaptic efficacy are some of the key early steps in the progression of Alzheimer’s disease(Selkoe, 2002, Ferreira and Klein, 2011).”
BackgroundMethodInfluentialFormaldehyde toxicity in age-related neurological dementia
Kou, Y., Zhao, H., Cui, D., Han, H., & Tong, Z. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101512 · Cited by 82
“the pathological process in AD patients (Ferreira and Klein, 2011).”
Amyloid-β and Tau Pathology of Alzheimer's Disease Induced by Diabetes in a Rabbit Animal Model
Bitel, C. L., Kasinathan, C., Kaswala, R. H., Klein, W. L., & Frederikse, P. H. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120571 · Cited by 78
Self-citationIslet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis?
Zhang, Y., & Song, W. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.001 · Cited by 79
“…Ab oligomers have been found to alter the composition, morphology and density of synapses, leading to the impairment of synaptic plasticity and cognitive function (Cleary et al., 2005; Ferreira and Klein, 2011; Lacor et al., 2007; Lesne et al., 2006; Shankar et al., 2008; Walsh et al., 2002).”
BackgroundHu, R., Wei, P., Jin, L. E., Zheng, T., Chen, W., Liu, X.-Y., Shi, X., Hao, J., Sun, N., & Gao, C. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.140 · Cited by 76
Batista, A. F., Bodart‐Santos, V., Felice, F. G. D., & Ferreira, S. T. (2018) · CNS Drugs · doi:10.1007/s40263-018-0593-6 · Cited by 78
Self-citationPrà, I. D., Chiarini, A., Gui, L., Chakravarthy, B., Pacchiana, R., Gardenal, E., Whitfield, J. F., & Armato, U. (2014) · The Neuroscientist · doi:10.1177/1073858414529828 · Cited by 79
Farr, S. A., Erickson, M. A., Niehoff, M. L., Banks, W. A., & Morley, J. E. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131883 · Cited by 72
“A and A oligomers play a major role in Alzheimer’s disease (AD) [2].”
Lourenco, M. V., Ferreira, S. T., & Felice, F. G. D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.03.003 · Cited by 74
Self-citationRamser, E. M., Gan, K. J., Decker, H., Fan, E. Y., Suzuki, M. M., Ferreira, S. T., & Silverman, M. A. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-12-0858 · Cited by 74
“…neurotoxins in AD, interact with glutamate receptors at the dendritic membrane, induce abnormal calcium influx and oxidative stress, block long-term potentiation (LTP), and facilitate long-term depression, ultimately leading to synapse failure (Ferreira and Klein, 2011; Benilova et al., 2012).”
Self-citationAn Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?
Sciaccaluga, M., Megaro, A., Bellomo, G., Ruffolo, G., Romoli, M., Palma, E., & Costa, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115991 · Cited by 70
Talwar, P., Sinha, J., Grover, S., Rawat, C., Kushwaha, S. S., Agarwal, R., Taneja, V., & Kukreti, R. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9390-0 · Cited by 71
Cremades, N., & Dobson, C. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.07.009 · Cited by 72
“…many studies have shown that soluble oligomers are themost toxic forms of amyloidogenic proteins, able to induce neurodegenerative processes (Benilova et al., 2012; Bucciantini et al., 2002; Ferreira and Klein, 2011; Hayden and Teplow, 2013; Sakono and Zako, 2010; Winner et al., 2011).”
Braidy, N., Zarka, M. H., Jugder, B., Welch, J. H., Jayasena, T., Chan, D. K. Y., Sachdev, P. S., & Bridge, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00177 · Cited by 70
“Similarly, a number of early-onset familial AD mutations display a more aggressive disease course and a greater propensity for Aβ to form soluble oligomeric Aβ aggregates (Ferreira and Klein, 2011; Streltsov et al., 2011; Wilcox et al., 2011).”
BackgroundWang, S., Yu, L., Yang, H., Li, C., Hui, Z., Xu, Y., & Zhu, X. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151397 · Cited by 72
Celecoxib Prevents Cognitive Impairment and Neuroinflammation in Soluble Amyloid β-treated Rats
Mhillaj, E., Morgese, M. G., Tucci, P., Furiano, A., Luongo, L., Bové, M., Maione, S., Cuomo, V., Schiavone, S., & Trabace, L. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2017.12.046 · Cited by 72
Panes-Fernández, J., Godoy, P. A., Silva-Grecchi, T., Celis, M. T., Ramírez-Molina, O., Gavilán, J., Muñoz-Montesino, C., Castro, P. A., Moraga‐Cid, G., Yévenes, G. E., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00709 · Cited by 71
Alternative Splicing in Alzheimer’s Disease
Love, J. E., Hayden, E. J., & Rohn, T. T. (2015) · Journal of Parkinson’s Disease and Alzheimer’s Disease · doi:10.13188/2376-922x.1000010 · Cited by 69
“The neuropathology of AD is characterized by both the accumulation of toxic, extracellular beta-amyloid deposition and neurofibrillary tangles resulting from an accumulation of hyperphosphorylated tau protein [3].”
BackgroundPDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition
Kroker, K. S., Mathis, C., Marti, A., Cassel, J., Rosenbrock, H., & Dorner‐Ciossek, C. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.03.023 · Cited by 69
“So far, no data have been published linking PDE9A inhibition to Ab, which is believed to be the putative cause of the AD pathophysiology because of its synaptotoxic features (Ferreira and Klein, 2011; Haass and Selkoe, 2007; Klein, 2013).”
Clinical Trials of Intravenous Immunoglobulin for Alzheimer’s Disease
Relkin, N. R. (2014) · Journal of Clinical Immunology · doi:10.1007/s10875-014-0041-4 · Cited by 67
“Soluble oligomeric forms of amyloid are extremely neurotoxic and are likely contribute to the pathogenesis of AD [14].”
Karisetty, B. C., Bhatnagar, A., Armour, E. M., Beaver, M., Zhang, H., & Elefant, F. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.577622 · Cited by 75
“Together, these findings support the concept that soluble APP and Aβ oligomers promote synaptic impairment and cognitive deficits during the early stages of AD, followed by neurodegeneration in the later stages (Ferreira and Klein, 2011).”
BackgroundWang, Y., Hu, H., Liu, X., & Guo, X. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1138499 · Cited by 68
Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy
Pérez-Garmendia, R., & Gevorkian, G. (2013) · Current Neuropharmacology · doi:10.2174/1570159x11311050004 · Cited by 65
“Extracellular and intraneuronal accumulation of amyloidbeta (A ) peptide aggregates in the brain has been hypothesized to play an important role in the neuropathology of Alzheimer’s Disease (AD) [1-7].”
BackgroundWestmark, C. J. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.122 · Cited by 63
Umeda, T., Ramser, E. M., Yamashita, M., Nakajima, K., Mori, H., Silverman, M. A., & Tomiyama, T. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0230-2 · Cited by 70
“According to one central view of AD pathogenesis, extracellular Aβ oligomers (eAβOs) bind plasma membrane targets to elicit pre- and postsynaptic intracellular effects (for reviews, [1, 2]).”
BackgroundThe neuronal insulin receptor in its environment
Gralle, M. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13909 · Cited by 64
“Since each of these proteins seems to be important for AbO binding, possibly several of them combine to form a macromolecular AbO receptor complex at the post-synaptic density, which might then affect and be affected by insulin signaling (Ferreira and Klein 2011).”
BackgroundCao, Z., Yang, J., Xu, R., Song, Q., Zhang, X., Liu, H., Qiang, X., Li, Y., Tan, Z., & Deng, Y. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.01.030 · Cited by 67
Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview
Bem, A. F. D., Krolow, R., Farias, H. R., de Rezende, V. L., Gelain, D. P., Moreira, J. C. F., Duarte, J. M. N., & de Oliveira, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.604150 · Cited by 69
Shi, X., Sun, K., Hu, R., Liu, X.-Y., Hu, Q., Sun, X., Yao, B., Sun, N., Hao, J., Wei, P., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1327-16.2016 · Cited by 63
“(ADDLs), seem to be the most neurotoxic species in AD and are more correlated with cellular and cognitive dysfunction than fibrils (Lambert et al., 1998; Glabe, 2006; Lesné et al., 2006; Ferreira and Klein, 2011).”
BackgroundFerreira, S. T. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12959 · Cited by 59
Self-citationThe Peculiar Role of the A2V Mutation in Amyloid-β (Aβ) 1–42 Molecular Assembly
Messa, M., Colombo, L., Favero, E. D., Cantú, L., Stoilova, T., Cagnotto, A., Rossi, A., Morbin, M., Fede, G. D., Tagliavini, F., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.576256 · Cited by 59
“Recently, A oligomers were identified as the main cause of synaptic dysfunction leading to alterations in both neuronal activity and cognitive function (31).”
BackgroundRoberts, J. P., Stokoe, S. A., Sathler, M. F., Nichols, R. A., & Kim, S. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100402 · Cited by 64
Paula-Lima, A. C., Adasme, T., & Hidalgo, C. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5796 · Cited by 59
Rohn, T. T. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140714908 · Cited by 58
A Mitocentric View of Alzheimer’s Disease
Hu, H., Tan, C., Tan, L., & Yu, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0117-7 · Cited by 58
Oh, J. H., Choi, J. S., & Nam, T. (2018) · Marine Drugs · doi:10.3390/md16100368 · Cited by 60
Smid, S. D., Mååg, J. L. V., & Musgrave, I. (2012) · Food & Function · doi:10.1039/c2fo30075c · Cited by 57
Caria, A. C. I., Nonaka, C. K. V., Cavalcante, B. R. R., Sousa, R. A. L. D., Aras, R., & Souza, B. S. D. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144977 · Cited by 57
“In an AD model, PE restored levels of non-protein thiols, preventing the accumulation of reactive oxygen species (ROS), increased SOD activity, prevented restored normal activity of glutathione reductase, glutathione peroxidase, and glutathione transferase, and suppressed TNF-α and IL-1β [215].”
BackgroundInfluentialAn update on potential links between type 2 diabetes mellitus and Alzheimer’s disease
Sousa, R. A. L. D., Harmer, A. R., Freitas, D. A., Mendonça, V. A., Lacerda, A. C. R., & Leite, H. R. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05693-z · Cited by 57
Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease
Gracia, P., Camino, J. D., Volpicelli‐Daley, L. A., & Cremades, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218043 · Cited by 57
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Self-citationMeng, P., Yoshida, H., Tanji, K., Matsumiya, T., Xing, F., Hayakari, R., Wang, L., Tsuruga, K., Tanaka, H., Mimura, J., et al. (2014) · Neuroscience Research · doi:10.1016/j.neures.2014.12.003 · Cited by 56
Aβ42 oligomers selectively disrupt neuronal calcium release
Lazzari, C., Kipanyula, M. J., Agostini, M., Pozzan, T., & Fasolato, C. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.020 · Cited by 55
van Groen, T., Schemmert, S., Brener, O., Gremer, L., Ziehm, T., Tusche, M., Nagel‐Steger, L., Kadish, I., Schartmann, E., Elfgen, A., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16565-1 · Cited by 53
Li, Q., Che, H., Wang, C., Zhang, L., Ding, L., Xue, C., Zhang, T., & Wang, Y. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800707 · Cited by 57
ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease
Krafft, G. A., Jerecı̀ć, J., Siemers, E., & Cline, E. N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.848215 · Cited by 54
“In the subsequent two decades, many studies across multiple disciplines have gathered extensive data that implicate AβOs as the causative AD structures, as discussed in a number of comprehensive reviews (Klein, 2002, 2006, 2013; Walsh and Selkoe, 2004, 2007; Viola et al., 2008; Krafft and Klein, 2010; Ondrejcak et al.…”
BackgroundAβ Oligomer Elimination Restores Cognition in Transgenic Alzheimer’s Mice with Full-blown Pathology
Schemmert, S., Schartmann, E., Zafiu, C., Kass, B., Hartwig, S., Lehr, S., Bannach, O., Langen, K., Shah, N. J., Kutzsche, J., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1209-3 · Cited by 53
Insulin and leptin as potential cognitive enhancers in metabolic disorders and Alzheimer's disease
Mejido, D. C. P., Peny, J. A., Vieira, M. N. N., Ferreira, S. T., & Felice, F. G. D. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108115 · Cited by 52
Self-citationAquaporin-4 and Cognitive Disorders
Wang, Y., Huang, C., Guo, Q., & Chu, H. (2022) · Aging and disease · doi:10.14336/ad.2021.0731 · Cited by 55
Hao, J.-R., Sun, N., Lei, L., Li, X.-Y., Yao, B., Sun, K., Hu, R., Zhang, X., Shi, X.-D., & Gao, C. (2015) · Cell Death & Disease · doi:10.1038/cddis.2015.315 · Cited by 53
“L-SPD may be explored as a potential therapeutic drug for AD.”
BackgroundInfluentialJohn, C. M., Yusof, N. I. S. M., Aziz, S. H. A., & Fauzi, F. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123894 · Cited by 52
“This suggests that sAPPα production is mediated by insulin [83] through the activation of insulin-signaling pathway [84,85].”
BackgroundThe Role of Astrocytes in the Development of the Cerebellum
Araújo, A. P. B., Carpi-Santos, R., & Gomes, F. C. A. (2019) · The Cerebellum · doi:10.1007/s12311-019-01046-0 · Cited by 55
Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease
Chiarini, A., Armato, U., Liu, D., & Dal Prà, I. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00134 · Cited by 51
“However, the earliest asymptomatic stages of AD are still hard to detect because the build-up of highly toxic, synapse destroying Aβ42-os inside and outside neurons and astrocytes is imperceptible until senile plaques and NFTs remain undetectable (West et al., 2004; Selkoe, 2008a,b; Ferreira and Klein, 2011; Klein, 20…”
BackgroundAquaporin-4 and Alzheimer’s Disease
Yang, C., Huang, X., Huang, X., Mai, H., Li, J., Jiang, T., Wang, X., & Lü, T. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150949 · Cited by 53
Buechler, J., & Salinas, P. C. (2018) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2018.00038 · Cited by 53
“Indeed, Aβ oligomers exert a multitude of synaptotoxic effects (Palop and Mucke, 2010; Ferreira and Klein, 2011; Tu et al., 2014; Forner et al., 2017).”
BackgroundSon, Y., Jeong, Y. J., Shin, N., Oh, S. J., Nam, K. R., Choi, H., Choi, J. Y., & Lee, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155553 · Cited by 53
Aoe, T. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01095 · Cited by 47
“The accumulation of misfolded proteins and ER stress are associated with neurodegenerative diseases such as Alzheimer's disease (Ferreira and Klein, 2011), Parkinson's disease (Gibb and Lees, 1988), amyotrophic lateral sclerosis (ALS) (Rosen et al., 1993), and prion disease (Park et al., 2017), as…”
BackgroundPimentel‐Coelho, P. M., Michaud, J.-P., & Rivest, S. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.025 · Cited by 51
Brain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer’s Disease
Sellés, M. C., Oliveira, M. M., & Ferreira, S. T. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179925 · Cited by 51
Self-citationThe Na+/Ca2+exchanger in Alzheimer’s disease
Pannaccione, A., Piccialli, I., Secondo, A., Ciccone, R., Molinaro, P., Boscia, F., & Annunziato, L. (2020) · Cell Calcium · doi:10.1016/j.ceca.2020.102190 · Cited by 52
Physical exercise protocols in animal models of Alzheimer’s disease: a systematic review
Sousa, R. A. L. D., Rodrigues, C. M., Mendes, B. F., Caria, A. C. I., Dias‐Peixoto, M. F., & Cassilhas, R. C. (2020) · Metabolic Brain Disease · doi:10.1007/s11011-020-00633-z · Cited by 54
Modulation of Amyloid‐β Aggregation by Histidine‐Coordinating Cobalt(III) Schiff Base Complexes
Heffern, M. C., Velasco, P. T., Matosziuk, L. M., Coomes, J. L., Karras, C. L., Ratner, M. A., Klein, W. L., Eckermann, A. L., & Meade, T. J. (2014) · ChemBioChem · doi:10.1002/cbic.201402201 · Cited by 50
Self-citationRohn, T. T. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/860959 · Cited by 51
Arrázola, M. S., Ramos‐Fernández, E., Cisternas, P., Ordenes, D., & Inestrosa, N. C. (2017) · PLoS ONE · doi:10.1371/journal.pone.0168840 · Cited by 49
Key Peptides and Proteins in Alzheimer’s Disease
Penke, B., Bogár, F., Paragi, G., Gera, J., & Fülöp, L. (2019) · Current Protein and Peptide Science · doi:10.2174/1389203720666190103123434 · Cited by 51
From beta amyloid to altered proteostasis in Alzheimer’s disease
Bruni, A. C., Bernardi, L., & Gabelli, C. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101126 · Cited by 47
Opportunities and challenges in developing relevant animal models for Alzheimer’s disease
Felice, F. G. D., & Munoz, D. P. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.01.006 · Cited by 50
Leithold, L. H. E., Jiang, N., Post, J., Ziehm, T., Schartmann, E., Kutzsche, J., Shah, N. J., Breitkreutz, J., Langen, K., Willuweit, A., et al. (2015) · Pharmaceutical Research · doi:10.1007/s11095-015-1791-2 · Cited by 47
Memantine prevents memory consolidation failure induced by soluble beta amyloid in rats
Tucci, P., Mhillaj, E., Morgese, M. G., Colaianna, M., Zotti, M., Schiavone, S., Cicerale, M., Trezza, V., Campolongo, P., Cuomo, V., et al. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00332 · Cited by 49
“Among others, glutamatergic receptors have been proposed as mediating the effect of Aβ on synaptic plasticity and memory (Klyubin et al., 2008; Ferreira and Klein, 2011).”
BackgroundJin, H., Komita, M., & Aoe, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00222 · Cited by 45
“…outside the cells is considered to cause toxicity with multiple mechanisms such as oxidative stress, mitochondrial dysfunction, synaptic dysfunction and effects on signaling pathways (e.g., insulin, Wnt; Alberdi et al., 2010; Saraiva et al., 2010; Ferreira and Klein, 2011; Arrázola et al., 2015).”
BackgroundAttia, H., Albuhayri, S., Alaraidh, S., Alotaibi, A., Yacoub, H. I., Mohamad, R. A., & Alamin, M. A. (2020) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.22519 · Cited by 47
Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism
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“Ab plaques initiates the pathological process of AD (Hardy and Higgins, 1992; Haass and Selkoe, 2007; Ferreira and Klein, 2011).”
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“…in life may influence how neurons interact with microglia and astrocytes, making cells over reactive when exposed to the amyloid-β peptide, which is generated in the brain under physiological conditions and form large extracellular deposits during disease development (Ferreira and Klein 2011).”
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“Ab oligomers, which are thought to induce detrimental signals in neurons (Ferreira and Klein 2011), were used to reproduce the increased levels of Ab peptides in mice.”
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“Recent evidences indicate that soluble Aβ oligomers rather than plaques determine cognitive decline (Lacor et al., 2007; Shankar et al., 2007; Ferreira and Klein, 2011) and that the severity of dementia in AD patients is strongly correlated with the levels of soluble Aβ oligomers (Lue et al.”
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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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