Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation

White, Anthony R.; Maher, Frances A.; Brazier, Marcus W.; Jobling, Michael F.; Thyer, James M.; Stewart, Leanne R.; Thompson, Andrew J.; Gibson, Riki; Masters, Colin L.; Multhaup, Gerd; Beyreuther, Konrad; Barrow, Colin J.; Collins, Steven J.; Cappai, Roberto

doi:10.1016/s0006-8993(02)04173-2

Cited by 28 publications

(22 citation statements)

References 64 publications

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“…A diverse range of fibrillar peptides that include Ab and human amylin can cause increased levels of APP, a putative Ab receptor [33], in both primary neuronal and astrocyte cultures [34]. Furthermore, there is increasing evidence that amylin, similar to Ab, can induce apoptotic cell death [35].…”

Section: Commonalities Of T2dm and Admentioning

confidence: 99%

Common features between diabetes mellitus and Alzheimer’s disease

Götz

Ittner

Lim

2009

Cell. Mol. Life Sci.

103

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Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer's disease (AD), both leading causes of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates - amylin in T2DM pancreatic islets, and beta-amyloid (Abeta) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with pancreatic beta-cell loss, and Abeta and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Abeta exert their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic properties are beneficial for both T2DM and AD.

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Section: Commonalities Of T2dm and Admentioning

confidence: 99%

Common features between diabetes mellitus and Alzheimer’s disease

Götz

Ittner

Lim

2009

Cell. Mol. Life Sci.

103

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“…We have recently examined whether APP processing and Dab1 phosphorylation are involved in cellular changes mediated by the synthetic peptide PrP(106-126) in vitro and by PrP sc in vivo in 263K scrapie-inoculated hamsters (Gavin et al, 2008). PrP(106-126) induces APP accumulation in cultured neurons (Gavin et al, 2008;White et al, 2003) but also reduces levels of CTF and A production (Gavin et al, 2008). However, these data need further corroboration in human CJD patients.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

Gavı́n¹,

Ferrer²,

Rı́o³

2010

Neurobiology of Disease

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Alzheimer's disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of Amyloid Precursor Protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in seventeen cases of sporadic CJD (sCJD) post mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrP sc types 1 and 2. One group, with PrP sc type 1 showed increased Dab1 phosphorylation, and lower CTF production with an absence of A deposition. The second sCJD group, which carried PrP sc type 2, showed lower levels of Dab1 phosphorylation and CTF production, and A deposition. Thus, the present observations suggest a correlation between Dab1-phosphorylation, A deposition and PrP sc type in sCJD.

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“…In addition, s-APP and h-APP also bind fibrils formed by several different amyloidogenic peptides, including Ab, amylin, and prion protein fragments (Lorenzo et al, 2000;White et al, 2003). These observations suggest that the binding of APP to fAb is conformation dependent rather than sequence dependent.…”

Section: Discussionmentioning

confidence: 93%

“…A previous study showed that yeast-purified s-APP directly binds fAb (White et al, 2003), and the binding of h-APP to fAb was described using detergent-soluble whole-membrane protein fractions. These observations suggest that, similarly to s-APP, membrane-associated h-APP should also bind fAb directly, although and indirect interaction mediated by an as yet unidentified protein intermediate cannot be ruled out.…”

Section: Resultsmentioning

confidence: 99%

Secreted amyloid precursor protein and holo‐APP bind amyloid β through distinct domains eliciting different toxic responses on hippocampal neurons

Kedikian

Heredia

Salvador

et al. 2010

J of Neuroscience Research

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Amyloid beta (Abeta) is a metabolic product of Abeta precursor protein (APP). Deposition of Abeta in the brain and neuronal degeneration are characteristic hallmarks of Alzheimer's disease (AD). Abeta induces neuronal degeneration, but the mechanism of neurotoxicity remains elusive. Increasing evidence implicates APP as a receptor-like protein for Abeta fibrils (fAbeta). In this study, we present further experimental support for the direct interaction of APP with fAbeta and for its involvement in Abeta neurotoxicity. Using recombinant purified holo-APP (h-APP), we have shown that it directly binds fAbeta. Employing deletion mutant forms of APP, we show that two different sequences are involved in the binding of APP to fAbeta. One sequence in the n-terminus of APP is required for binding of fAbeta to secreted APP (s-APP) but not to h-APP. In addition, the extracellular juxtamembrane Abeta-sequence mediates binding of fAbeta to h-APP but not to s-APP. Deletion of the extracellular juxtamembrane Abeta sequence abolishes abnormal h-APP accumulation and toxicity induced by fAbeta deposition, whereas deletions in the n-terminus of APP do not affect Abeta toxicity. These experiments show that interaction of toxic Abeta species with its membrane-anchored parental protein promotes toxicity in hippocampal neurons, adding further support to an Abeta-receptor-like function of APP directly implicated in neuronal degeneration in AD.

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Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation

Cited by 28 publications

References 64 publications

Common features between diabetes mellitus and Alzheimer’s disease

Common features between diabetes mellitus and Alzheimer’s disease

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

Secreted amyloid precursor protein and holo‐APP bind amyloid β through distinct domains eliciting different toxic responses on hippocampal neurons

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