The Carboxyl Termini of β-Amyloid Peptides 1-40 and 1-42 Are Generated by Distinct γ-Secretase Activities

Klafki, Hans-W.; Abramowski, Dorothée; Swoboda, Robert; Paganetti, Paolo; Staufenbiel, Matthias

doi:10.1074/jbc.271.45.28655

Cited by 164 publications

(156 citation statements)

References 32 publications

(38 reference statements)

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“…This is consistent with the recent finding that the ␥-secretase cleavage at position 40 and 42 can be inhibited differentially with the protease inhibitor MDL 28170 (26,27). Moreover, as discussed by Tischer and Cordell (28) the cleavage at position 42 might be facilitated within the ER and early Golgi, because the lower membrane thickness may allow proteases located on the cytoplasmic site of the ER to cleave at position 42, a hypothesis supported by our data.…”

Section: A␤42 Generation and Accumulation 16087supporting

confidence: 81%

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

Wild-Bode¹,

Yamazaki²,

Capell³

et al. 1997

Journal of Biological Chemistry

302

214

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Section: A␤42 Generation and Accumulation 16087supporting

confidence: 81%

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

Wild-Bode¹,

Yamazaki²,

Capell³

et al. 1997

Journal of Biological Chemistry

302

214

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“…␥-Secretase inhibitors mimic the effects of pathogenic PS mutations. The graph depicts schematically the effects of increasing concentrations of ␥-secretase inhibitors on A␤40 and A␤42 production, based on data from published reports (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Similar findings have been reported with inhibitors of different structural classes, assayed in either cell culture systems or partially purified membrane preparations.…”

Section: Fad-linked Ps Mutations Impairsupporting

confidence: 64%

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Shen

Kelleher

2007

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

427

358

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Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

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“…The suggestion applies to secreted A␤, as is the case for previous work on this question (14,15), but does not address the nature of the protease or proteases responsible for intracellular formation of A␤ variants (38,39). The possibility that secreted A␤40 and A␤42 are generated by two distinct but closely related proteases with very similar inhibitor sensitivities cannot be ruled out but may be addressed by applying the approach described here to a larger and more structurally diverse set of more potent protease inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

Durkin¹,

Murthy²,

Husten³

et al. 1999

Journal of Biological Chemistry

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The Alzheimer's disease amyloid peptide A␤ has a heterogeneous COOH terminus, as variants 40 and 42 residues long are found in neuritic plaques and are secreted constitutively by cultured cells. The proteolytic activity that liberates the A␤ COOH terminus from the ␤-amyloid precursor protein is called ␥-secretase. It could be one protease with dual specificity or two distinct enzymes. By using enzyme-linked immunosorbent assays selective for A␤40 or A␤42, we have measured A␤ secretion by a HeLa cell line, and we have examined the dose responses for a panel of five structurally diverse ␥-secretase inhibitors. The inhibitors lowered A␤ and p3 secretion and increased levels of the COOH-terminal 99-residue ␤-amyloid precursor protein derivative that is the precursor for A␤ but did not alter secretion of ␤-amyloid precursor protein derivatives generated by other secretases, indicating that the inhibitors blocked the ␥-secretase processing step. The dose-dependent inhibition of A␤42 was unusual, as the compounds elevated A␤42 secretion at sub-inhibitory doses and then inhibited secretion at higher doses. A compound was identified that elevated A␤42 secretion at a low concentration without inhibiting A␤42 or A␤40 at high concentrations, demonstrating that these phenomena are separable pharmacologically. Using either of two methods, IC 50 values for inhibition of A␤42 and A␤40 were found to have the same rank-order and fall on a trend line with near-unit slope. These results favor the hypothesis that A␤ variants ending at residue 40 or 42 are generated by a single ␥-secretase.A hallmark feature of the neuropathology of Alzheimer's disease is the abundant deposition of amyloid into neuritic and diffuse plaques in the brain parenchyma. The predominant core constituent of amyloid plaques is a 40-to 42-residue amyloid peptide, A␤.1 A␤ is generated from the ␤-amyloid precursor protein (APP) by two sequential proteolytic cleavages. First, ␤-secretase activity liberates the NH 2 terminus of A␤, generating a 99-residue COOH-terminal APP fragment (C99). Second, ␥-secretase activity cleaves C99 to liberate the A␤ COOH terminus. APP is also processed in a nonamyloidogenic manner, being cleaved within the A␤ domain by an activity termed ␣-secretase. The terms ␣-, ␤-, and ␥-secretase are conceptual terms for proteases that are not yet definitively identified (reviewed in Refs. 1-3).The A␤ peptide is a constitutive secretory product of a variety of neuronal and non-neuronal cells, in which multiple NH 2 -and COOH-terminal cleavages generate several A␤ species. The most prevalent secreted forms of A␤ appear identical to neuritic plaque core amyloid A␤ and terminate either at residue 40 or 42 (4, 5). Although A␤40 variants are the predominant component of soluble A␤ extracted from brain and secreted by cultured cells, A␤42 forms are the predominant constituents of neuritic plaques (6 -9). In vitro, forms of A␤ that terminate at residue 42 form fibril faster than forms of A␤ that terminate at residue 40, by orders of magnitude (10). Mut...

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The Carboxyl Termini of β-Amyloid Peptides 1-40 and 1-42 Are Generated by Distinct γ-Secretase Activities

Cited by 164 publications

References 32 publications

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

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

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

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