The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease

May combine two claims.

Memory loss was reversed in APP transgenic mice injected with antibodies against Aβ, and this reversal did not require removal of amyloid plaques.

“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).”

• cites Dodart et al., 2002 sourceNot checked yet

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May combine two claims.

Clusterin prevents amyloid formation and promotes accumulation of soluble Aβ oligomers.

“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).”

• cites Lambert et al., 1998 sourceNot checked yet

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Probably not a substantial claim: may not pass S1 (asserted).

Plaque load is a poor correlate of cognitive function in AD.

“some neuropathologists rejected the hypothesis, emphasizing that a poor correlation exists between plaque load and cognitive function (Terry et al., 1994).”

• cites Terry et al., 1994Not checked yet

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May combine two claims.

With chronic exposure, Aβ oligomers ultimately kill neurons, selectively for vulnerable subpopulations, and this death is prevented by knockout of Fyn.

“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.”

• cites Lambert et al., 1998 sourceNot checked yet

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May combine two claims.

The oligomer hypothesis predicted that early memory loss should be reversible, and this prediction was confirmed in transgenic mouse experiments.

“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).”

• cites Dodart et al., 2002 sourceNot checked yet

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• cites Kotilinek et al., 2002 sourceNot checked yet

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May combine two claims.

Aβ oligomers inhibit functional synaptic plasticity (long-term potentiation) within minutes without affecting baseline excitability.

“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.”

• cites Lambert et al., 1998 sourceNot checked yet

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May combine two claims.

Aβ oligomers associate with neurons, accumulating very early in disease progression, in loci distinct from amyloid deposits.

“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).”

• cites Lacor et al., 2004 sourceNot checked yet

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• cites Kayed et al., 2003 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

It is uncertain whether one class of Aβ oligomer size is more germane to pathogenesis than another.

“At present it is uncertain whether one class is more germane to pathogenesis than another.”

May combine two claims.

At sub-nanomolar doses, Aβ markedly enhances LTP, an effect that occurs over a narrow range of concentrations and is associated with presynaptic activation of alpha7 nicotinic receptors.

“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.”

• cites Puzzo et al., 2008 sourceNot checked yet

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May combine two claims.

Not all Aβ oligomers are toxic, even those of a given size; subtle conformation changes affect toxicity and immunoreactivity.

“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).”

• cites Chromy et al., 2003 sourceNot checked yet

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• cites Pitt et al., 2009 sourceNot checked yet

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May combine two claims.

Traumatic brain injury is associated with acutely elevated Aβ oligomer levels in CSF, with a positive correlation between oligomer levels and severity of sequelae.

“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).”

• cites David Brody, MP Lambert, and WL Klein, unpublishedNot checked yet

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May combine two claims.

In familial AD, metabolic effects of mutations promote increased levels of total Aβ, or increased Aβ42 to Aβ40 ratio, conditions that favor oligomerization.

“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.”

• cites Borchelt et al., 1996 sourceNot checked yet

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• cites Citron et al., 1992 sourceNot checked yet

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May combine two claims.

More generalized neuronal impacts of Aβ oligomers include Ca2+ dyshomeostasis, oxidative stress and mitochondrial damage, proteasome inhibition, tau accumulation and hyperphosphorylation, impairment of fast axonal transport, ER stress, cell cycle re-entry and ultimately cell death.

“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.”

May combine two claims.

Memory failure in transgenic mice coincides with the appearance of SDS-stable 12mers, which is compelling in situ evidence that this species is pathogenic.

“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).”

• cites Lesne et al., 2006 sourceNot checked yet

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May combine two claims.

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.

“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).”

• cites Giuffrida et al., 2009 sourceNot checked yet

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May combine two claims.

Transgenic mouse AD models manifest a spontaneous age-onset impairment of LTP that presumably is linked to impaired performance in memory tests.

“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).”

• cites Gong et al., 2004 sourceNot checked yet

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• cites Arendash et al., 2001 sourceNot checked yet

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May combine two claims.

Synapse-specific effects of Aβ oligomers include alterations in neurotransmitter (glutamate/D-serine) levels, down-regulation of plasticity-related receptors at the plasma membrane, altered plasticity, cytoskeletal abnormalities and synapse loss.

“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.”

May combine two claims.

The oligomer hypothesis attributes early memory loss to oligomer-induced disruption of synaptic plasticity, and later stages of dementia to oligomer-induced cellular degeneration and death.

“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.”

• AssumptionRests on an assumption: Early AD is largely a disease of memory formation, and memory dysfunction is the primary symptom bringing patients to physicians.

May combine two claims.

While Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent.

“Thus, while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent.”

May combine two claims.

AD memory failure is caused by small soluble oligomers of the Aβ peptide, which target and disrupt particular synapses.

“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.”

• AssumptionRests on an assumption: Early AD is largely a disease of memory formation, and memory dysfunction is the primary symptom bringing patients to physicians.
• AssumptionRests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.

May combine two claims.

Aβ oligomers can be neurologically significant toxins, possibly the most important ones for AD.

“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.”

• AssumptionRests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.

May combine two claims.

The most pathogenically relevant Aβ-derived toxins are small soluble oligomers, not readily detected.

“it now appears the most pathogenically relevant Aβ-derived toxins are small soluble oligomers, not readily detected.”

• AssumptionRests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.

Classified as probably not a substantial claim.

The original amyloid cascade hypothesis attributed dementia to nerve cell death caused by the toxicity of large insoluble amyloid fibrils.

“The hypothesis attributed dementia to nerve cell death caused by the toxicity of large insoluble amyloid fibrils.”

• cites Hardy and Higgins, 1992 sourceNot checked yet

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May combine two claims.

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, supporting the concept that Aβ oligomers provide a unifying mechanism for initiation of AD pathogenesis.

“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.”

• AssumptionRests on an assumption: AD can be attributed to a single disease-initiating cytotoxin, albeit one likely elicited by multiple factors.

May combine two claims.

Serine phosphorylation precludes tyrosine phosphorylation of IRS-1, blocking downstream insulin signaling.

“Serine phosphorylation precludes tyrosine phosphorylation of IRS-1, blocking downstream insulin signaling.”

Classified as probably not a substantial claim.

Physiologically, IRS-1 is phosphorylated at tyrosine residues by the tyrosine kinase activity of the insulin receptor, which activates downstream signaling in the insulin pathway.

“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).”

• cites Araki et al., 1994 sourceNot checked yet

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• cites White, 2003 sourceNot checked yet

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May combine two claims.

Insulin receptors are present in the brain, where they are abundantly distributed in synaptic membranes of the cerebral cortex and hippocampus.

“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).”

• cites Abbott et al., 1999 sourceNot checked yet

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• cites Havrankova et al., 1981 sourceNot checked yet

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• cites Marks et al., 1990 sourceNot checked yet

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May combine two claims.

Aβ oligomers induce a striking redistribution of insulin receptors, causing their internalization from dendritic membranes and accumulation in the cell body, which renders neurons insulin resistant.

“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).”

• cites De Felice et al., 2009 sourceNot checked yet

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• cites De Felice et al., 2008 sourceNot checked yet

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• cites Zhao et al., 2008 sourceNot checked yet

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May combine two claims.

Brain insulin signaling declines with age, and this is the primary risk factor for Alzheimer's disease.

“Brain insulin signaling declines with age (Frolich et al., 1998; , 1999; Hoyer, 1998; Rivera et al., 2005), the primary risk factor for AD.”

• cites Frolich et al., 1998 sourceNot checked yet

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• cites Hoyer, 1998 sourceNot checked yet

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• cites Rivera et al., 2005 sourceNot checked yet

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May combine two claims.

Type 2 diabetes patients have an elevated risk for Alzheimer's disease and manifest deficient CNS insulin signaling, likely because of decreased insulin uptake into the brain following sustained peripheral hyperinsulinemia.

“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).”

• cites Matsuzaki et al., 2010 sourceNot checked yet

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• cites Ott et al., 1999 sourceNot checked yet

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• cites Toro et al., 2009 sourceNot checked yet

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May combine two claims.

Insulin receptor internalization occurs by a mechanism mediated by casein kinase 2 and Ca2+/calmodulin-dependent kinase 2, which also are involved in ADDL-induced internalization of NMDA receptors.

“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).”

• cites De Felice et al., 2009 sourceNot checked yet

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May combine two claims.

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.

“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)).”

• cites Lacor et al., 2004 sourceNot checked yet

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May combine two claims.

Physiological insulin signaling may play an important role in defending neurons against Alzheimer's disease, suggesting that loss of CNS insulin signaling in aging and diabetes is a potential risk factor for Alzheimer's disease.

“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.”

May combine two claims.

When given to subjects with early Alzheimer's disease, intranasal insulin improves performance but only at higher doses, consistent with expected insulin resistance and suggesting possible involvement of additional mechanisms other than stimulation of plasticity.

“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.”

• cites Reger et al., 2008bNot checked yet

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May combine two claims.

Aβ oligomers induce a marked removal of insulin receptors from synapses, decreasing the responsiveness of nerve cells to insulin.

“Aβ oligomers induce a marked removal of IRs from synapses, decreasing the responsiveness of nerve cells to insulin.”

May combine two claims.

Rosiglitazone potentiates the ability of insulin to protect synapses against Aβ oligomers, while a cell-permeant inhibitor of the tyrosine kinase activity of the insulin receptor abrogates the protection by insulin.

“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.”

May combine two claims.

Insulin itself blocks the pathological binding of Aβ oligomers and the resulting redistribution of insulin receptors and synapse loss.

“insulin itself blocks the pathological binding of Aβ oligomers and the resulting redistribution of IRs and synapse loss (De Felice et al., 2009).”

• cites De Felice et al., 2009 sourceNot checked yet

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May combine two claims.

Antibodies can reverse intracellular tau and synapse pathology and provide cognitive benefits.

“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).”

• cites Chauhan et al., 2008Not checked yet

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• cites Oddo et al., 2006 sourceNot checked yet

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• cites Hillen et al., 2010 sourceNot checked yet

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May combine two claims.

Stimulation of insulin signaling protects against accumulation of hyperphosphorylated tau, a pathological hallmark of Alzheimer's disease that is induced by Aβ oligomers.

“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).”

• cites Escribano et al., 2010 sourceNot checked yet

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• cites De Felice et al., 2008 sourceNot checked yet

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May combine two claims.

The mechanism by which insulin protects does not involve direct competition between Aβ oligomers and insulin for a common binding site on the neuronal surface; rather, it consists of an insulin receptor signaling-dependent down-regulation of neuronal ADDL binding sites.

“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.”

May combine two claims.

Clustering of oligomers at synapses shows a cause-and-effect relationship with characteristic Alzheimer neuropathologies: AD-type tau hyperphosphorylation, redistribution of insulin receptors, spine loss and oxidative stress are manifest exclusively in neurons showing synapses targeted by oligomers.

“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”

• cites De Felice et al., 2008 sourceNot checked yet

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• cites De Felice et al., 2009 sourceNot checked yet

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• cites Lacor et al., 2007 sourceNot checked yet

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May combine two claims.

The peri-somatic distribution in human brain is evident in the complete absence of amyloid plaques, indicating that oligomer pathology occurs early in the disease process.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The pattern of oligomer binding depends on cell maturation.

“As expected, the pattern of binding depends on cell maturation.”

May combine two claims.

Oligomer-targeted neurons are distributed sparsely, indicating that oligomers might originate within the cells they surround.

“These oligomer-targeted neurons are distributed sparsely, indicating oligomers might originate within the cells they surround (Figure 1, right).”

May combine two claims.

Oligomers are gain-of-function pathogenic ligands that target and disrupt signaling at particular synapses, a specificity that may explain why early Alzheimer's disease is a disease of memory.

“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.”

May combine two claims.

Aβ oligomers bind with nanomolar affinity to cellular prion protein (PrPC), and anti-PrP antibodies reduce oligomer binding to neurons and rescue synaptic plasticity.

“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).”

• cites Lauren et al., 2009 sourceNot checked yet

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May combine two claims.

Some neurons are targeted by oligomers while others are not, establishing clear-cut specificity.

“Significantly, some neurons are targeted while others are not, establishing clear-cut specificity.”

May combine two claims.

EphB2 receptors interact functionally and physically with NMDARs at synapses.

“EphB2 receptors interact functionally and physically with NMDARs at synapses”

May combine two claims.

Other putative receptors/co-receptors involved in neuronal binding of Aβ oligomers include the p75 neurotrophin receptor, RAGE, nicotinic acetylcholine receptors and Frizzled.

“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).”

• cites Knowles et al., 2009 sourceNot checked yet

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• cites Sturchler et al., 2008 sourceNot checked yet

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• cites Magdesian et al., 2005 sourceNot checked yet

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May combine two claims.

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.

“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.”

May combine two claims.

NMDARs are necessary but not sufficient for ADDL binding.

“These observations indicate that NMDARs are necessary but not sufficient for ADDL binding”

Classified as probably not a substantial claim.

Initial ADDL binding recruits more PrPC molecules to form a higher order complex that may initiate toxic signaling at the neuronal membrane.

“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”

• cites Caetano et al., 2011 sourceNot checked yet

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May combine two claims.

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.

“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).”

• cites De Felice et al., 2007 sourceNot checked yet

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May combine two claims.

NMDAR knock-down abrogates neuronal oxidative stress induced by Aβ oligomers, which is mediated by aberrant activation of NMDARs.

“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).”

• cites De Felice et al., 2007 sourceNot checked yet

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May combine two claims.

A second prediction based on altered Arc expression is that oligomers would induce aberrant dendritic spine morphology, and this has been confirmed in culture and in situ.

“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).”

• cites Lacor et al., 2007 sourceNot checked yet

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• cites Ma et al., 2009Not checked yet

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May combine two claims.

Although receptors are lost from the surface, total levels are at first unchanged, indicating dysfunctional trafficking.

“Although receptors are lost from the surface, total levels are at first unchanged, indicating dysfunctional trafficking”

May combine two claims.

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.

“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.”

May combine two claims.

Aβ oligomers initially diffuse as if bound to an untethered protein; within minutes, movement slows and oligomers become immobilized, typically at active synapses labeled with FM4-64; synaptic trapping is accompanied by co-clustering and immobilization of mGluR5 metabotropic glutamate receptors.

“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.”

• cites Renner et al., 2010 sourceNot checked yet

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May combine two claims.

Because Arc is an actin binding protein, its aberrant expression was predicted to disrupt receptor trafficking, which could consequently disrupt plasticity.

“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).”

• cites Lacor et al., 2004 sourceNot checked yet

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• cites Gong et al., 2003 sourceNot checked yet

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May combine two claims.

Knocking down NMDARs or PrPC, or adding antibodies against their extracellular domains, blocks the accumulation of ADDL clusters at synapses.

“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).”

• cites De Felice et al., 2007 sourceNot checked yet

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• cites Decker et al., 2010aNot checked yet

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• cites Lauren et al., 2009 sourceNot checked yet

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May combine two claims.

Within minutes of exposure to oligomers, neurons show a localized over-expression of Arc, which later spreads ectopically throughout the dendrite.

“Within minutes of exposure to oligomers, neurons show a localized over-expression of Arc, which later spreads ectopically throughout the dendrite.”

May combine two claims.

Arc is an immediate early gene product that is translated from mRNA in dendritic spines.

“Arc is an immediate early gene product that is translated from mRNA in dendritic spines (Bramham, 2008).”

• cites Bramham, 2008 sourceNot checked yet

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May combine two claims.

The mechanism of oligomer synapto-toxicity appears to be tied closely to accumulation of excessive levels of Ca++, consistent with involvement of NMDA and mGluR5 receptors.

“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.”

• cites Marx, 2007 sourceNot checked yet

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Classified as probably not a substantial claim.

Interaction with Aβ oligomers could potentially dysregulate such signaling pathways, resulting in neurotoxicity.

“Interaction with Aβ oligomers could potentially dysregulate such signaling pathways, resulting in neurotoxicity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

PrPC has been proposed to act as a cell-surface platform that orchestrates several physiological signaling pathways at the neuronal plasma membrane.

“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)).”

• cites Linden et al., 2008 sourceNot checked yet

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• cites Martins et al., 2010Not checked yet

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May combine two claims.

The consequent chronic mGluR5 activity would keep FMRP dephosphorylated and eliminate the ability of FMRP to repress mRNA translation.

“The consequent chronic mGluR5 activity would keep FMRP dephosphorylated and eliminate the ability of FMRP to repress mRNA translation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Such aberrant spines also are seen in traumatic brain injury and prionoses.

“Such aberrant spines also are seen in traumatic brain injury and prionoses (Fiala et al., 2002).”

• cites Fiala et al., 2002 sourceNot checked yet

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May combine two claims.

Fragile X leads to hyperactivity in the protein phosphatase PP2a, which inactivates MAPK, an enzyme with impaired activity in oligomer-exposed neurons.

“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).”

• cites Kim et al., 2008 sourceNot checked yet

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• cites Tong et al., 2001 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Hyperactivity of mGluR5 receptors caused by oligomers is due to a clustering mechanism, and this receptor state hypothetically could be insensitive to negative feedback by FMRP.

“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.”

May combine two claims.

Spines after short-term exposure to oligomers are long and spindly, resembling immature spines that express low levels of AMPA receptors.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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.”

May combine two claims.

This mechanism is analogous to the clustering of receptors at immunological synapses during T cell activation, with the fundamental difference that oligomer-induced clustering is toxic.

“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.”

• cites Douglass and Vale, 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

FMRP's control of Arc is a prime example of its role in mRNA trafficking and expression.

“Its control of Arc is a prime example (Iacoangeli et al., 2008).”

• cites Iacoangeli et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Eventually, spines deteriorate and synapses are lost, consistent with low levels of Arc found in mature transgenic mice.

“Eventually, spines deteriorate and synapses are lost, consistent with low levels of Arc found in mature tg-mice (Chin et al., 2005).”

• cites Chin et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites Bear et al., 2004 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Fragile X Syndrome is a developmental disorder caused by inability to express the regulatory protein FMRP.

“Fragile X is a developmental disorder caused by inability to express the regulatory protein FMRP.”

May combine two claims.

Drebrin becomes greatly diminished in culture and in transgenic mice.

“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).”

• cites Lacor et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Calon et al., 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Clustering can be elicited by mGluR5 antibodies, and antibody-induced clustering mimics the effects of oligomers in causing elevated Ca++ and synapse deterioration.

“Clustering can be elicited by mGluR5 antibodies, and antibody-induced clustering mimics the effects of oligomers in causing elevated Ca++ and synapse deterioration.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

There is reason to believe that non-pharmacological approaches based on these novel findings might be beneficial to ameliorate Alzheimer's disease symptoms.

“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).”

• cites Schaeffer et al., 2009 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Coupled with the potential of dendrites for activity-stimulated exocytosis, such a phenomenon could account for the perineuronal deposits of oligomers seen in Figure 1.

“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).”

• cites Kennedy et al., 2010 sourceNot checked yet

  Not checked in the free run.

• cites Lacor et al., 2004 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Exercise and a balanced diet might have positive effects on both peripheral and brain insulin signaling.

“For example, exercise and a balanced diet might have positive effects on both peripheral and brain insulin signaling.”

Classified as probably not a substantial claim.

One implication is that D1/D5 receptors may constitute a target for the development of novel approaches to combat synapse failure in Alzheimer's disease.

“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.”

Classified as probably not a substantial claim.

The discovery that insulin resistance plays an important role in the pathogenesis of Alzheimer's disease suggests that strategies aimed to bolster brain insulin signaling might be beneficial in preventing synapse failure and neuronal damage in Alzheimer's disease.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dopaminergic neurotransmission, centrally implicated in the brain reward system and known to decline with aging, plays important roles in non-pharmacological strategies aimed to improve age-related cognitive decline, such as environmental enrichment and physical exercise.

“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).”

• cites De Keyser et al., 1990 sourceNot checked yet

  Not checked in the free run.

• cites van Praag et al., 2000 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Oligomer-induced hyperactivity of mGluR5 in Alzheimer's disease would thus promote production of even more Aβ and oligomers.

“Oligomer-induced hyperactivity of mGluR5 in Alzheimer’s disease would thus promote production of even more Aβ and oligomers.”

May combine two claims.

A connection has recently been established between dopaminergic signaling and Alzheimer's disease, 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.

“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).”

• cites Jurgensen et al., 2011 sourceNot checked yet

  Not checked in the free run.