Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42

Wild-Bode, Christine; Yamazaki, Tsuneo; Capell, Anja; Leimer, Uwe; Steiner, Harald; Ihara, Yasuo; Haass, Christian

doi:10.1074/jbc.272.26.16085

Cited by 302 publications

(237 citation statements)

References 32 publications

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“…To further demonstrate that an acidic cellular compartment is required for Gleevec's effects on APP metabolism, we exposed N2a 695 cells to the alkalizing agent NH 4 Cl to raise the pH of otherwise acidic intracellular compartments (32). Like bafilomycin A1, NH 4 Cl prevented Gleevec from inducing APP-C140 or the 10-kDa APP-CTF (Fig.…”

Section: Resultsmentioning

confidence: 99%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Section: Resultsmentioning

confidence: 99%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…They have recovered A␤40 and A␤42 from lysates of NT2 neuroblastoma cells that were concentrated in fractions enriched in Golgi and endoplasmic reticulum (18). Others have found in cultured cells intracellular A␤ accumulation derived from the Golgi network and endoplasmic reticulum (18,(22)(23)(24)(25)(26). Piccini et al (27), using immunoprecipitation, have identified A␤ species in soluble extracts of frozen AD and control brain (27,28), but did not examine for tau complexes.…”

Section: Discussionmentioning

confidence: 99%

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Jian-ping

Arai

Miklóssy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

217

202

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To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-␤ protein (A␤). This complex enhances tau phosphorylation by GSK3␤, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A␤ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A␤ peptides in the mid to C-terminal regions of A␤. This binding is also significantly decreased by GSK3␤ phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A␤ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A␤ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and A␤ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A␤ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A␤ nucleation. Blocking the sites where A␤ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.immunochemistry ͉ neurofibrillary tangles ͉ senile plaques ͉ surface plasmon resonance S o far, no reasonable interpretation has been advanced to explain the simultaneous appearance of senile plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Senile plaques develop extracellularly with the main component being aggregated amyloid-␤ protein (A␤), whereas NFTs develop intracellularly with the main component being aggregated forms of phosphorylated tau. The two aggregation processes appear to occur independently, because NFTs develop in neuronal cell bodies and senile plaques develop around their nerve endings. This observation has led to two schools of thought regarding AD causation. The tau hypothesis holds that the disease is driven by tangles resulting from an excess of tau phosphorylation or a deficiency of its dephosphorylation (1). The hypothesis does not explain plaques. The amyloid hypothesis holds that the disease is driven by excess production of A␤ (2, 3). This hypothesis does not explain NFTs. Nevertheless, the amyloid cascade hypothesis is dominant because mutations in amyloid precursor protein (APP), which enhance A␤ production, cause autosomal dominant AD but not other types of dementia (2). On the other hand, mutations in tau that promote tau aggregation produce autosomal dominant frontotemporal dementia but not AD (4, 5). As a result, the presumption is that excess A␤ is a major cause and an upstream event of AD tangle formation, but exactly how an A␤ excess ...

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“…3A). It has been suggested that A␤ and A␤ are generated in different cell compartments and that A␤ 1-42 is mainly generated in the ER (16,17). Furthermore, peptide aldehyde ␥-secretase inhibitors differentially block production of secreted A␤ relative to secreted A␤ and, at some doses, can stimulate production of A␤ 1-42 while inhibiting A␤ 1-40 generation (18 -21).…”

Section: App Undergoesmentioning

confidence: 99%

Caspase Activation Increases β-Amyloid Generation Independently of Caspase Cleavage of the β-Amyloid Precursor Protein (APP)

Tesco

Koh

Tanzi

2003

Journal of Biological Chemistry

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The amyloid precursor protein (APP) undergoes "alternative" proteolysis mediated by caspases. Three major caspase recognition sites have been identified in the APP, i.e. one at the C terminus (Asp 720 ) and two at the N terminus (Asp 197 and Asp 219 ). Caspase cleavage at Asp 720 has been suggested as leading to increased production of A␤. Thus, we set out to determine which putative caspase sites in APP, if any, are cleaved in Chinese hamster ovary cell lines concurrently with the increased A␤ production that occurs during apoptosis. We found that cleavage at Asp 720 occurred concurrently with caspase 3 activation and the increased production of total secreted A␤ and A␤ 1-42 in association with staurosporineand etoposide-induced apoptosis. To investigate the contribution of caspase cleavage of APP to A␤ generation, we expressed an APP mutant truncated at Asp 720 that mimics APP caspase cleavage at the C-terminal site. This did not increase A␤ generation but, in contrast, dramatically decreased A␤ production in Chinese hamster ovary cells. Furthermore, the ablation of caspasedependent cleavage at Asp 720 , Asp 197 , and Asp 219 (by sitedirected mutagenesis) did not prevent enhanced A␤ production following etoposide-induced apoptosis. These findings indicate that the enhanced A␤ generation associated with apoptosis does not require cleavage of APP at its C-terminal (Asp 720 ) and/or N-terminal caspase sites.Alzheimer's disease (AD) 1 is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. AD is characterized by ␤-amyloid deposition, intracellular neurofibrillary tangles, and extensive loss of neurons. Amyloid plaques are formed by aggregates of amyloid-␤-peptide, a 37-43 amino acid fragment (primarily A␤ 40 and A␤ 42 ) generated by proteolytic processing of the amyloid precursor protein (APP). APP is cleaved sequentially by ␤-secretase and ␥-secretase to release A␤ constitutively from neuronal and non-neuronal cells. APP proteolysis by ␤-and ␣-secretases results in the production of ␤-and ␣-APP secreted fragments (APPs) as well as the C99 and C83 APP-C-terminal fragments (APP-CTFs), respectively. The C99 and C83 APP-CTFs then serve as substrates for ␥-secretase, resulting in the production of A␤ or p3, respectively (1). In addition to the normal APP processing, "alternative" processing of APP by caspases has also been reported. Apoptosis is a form of cell death triggered by the activation of an intrinsic cellular program deliberately invoked by the cell in response to environmental and or developmentally associated signals (2). The death machinery can be activated by diverse stimuli and has as its central component a group of proteolytic enzymes called caspases. Caspases exhibit primary specificity for aspartic acid residues (3). To date, more then 280 proteins have been shown to be substrates of one or more caspases in mammalian cells. Among them are proteins involved in cell death, cell cycle regulation, cytoskeleton organization, DNA an...

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Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42

Cited by 302 publications

References 32 publications

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Caspase Activation Increases β-Amyloid Generation Independently of Caspase Cleavage of the β-Amyloid Precursor Protein (APP)

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