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

Durkin, John T.; Murthy, S. N. Prasanna; Husten, E J; Trusko, Stephen P.; Savage, Mary J.; Rotella, David P.; Greenberg, Barry D.; Siman, Robert

doi:10.1074/jbc.274.29.20499

Cited by 45 publications

(37 citation statements)

References 40 publications

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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: 59%

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.

431

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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Section: Fad-linked Ps Mutations Impairsupporting

confidence: 59%

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.

431

358

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“…The peptide aldehydes and peptidomimetic inhibitors containing a difluoroketone or alcohol group increase A␤42 secretion at sub-inhibitory doses and diminish it at a high concentration, whereas they inhibit A␤40 generation in an absolutely dose-dependent manner (39 -41). However, the rank order of inhibitory potencies of several peptide aldehydes against A␤40 and A␤42 are at similar levels, suggesting that a single ␥-secretase complex would generate A␤40 and A␤42 (40). In addition, the transition state analogue inhibitors of aspartyl proteases containing a hydroxyethylene isostere also inhibited the secretion of A␤40 and A␤42 to similar extents (12,41).…”

Section: Discussionmentioning

confidence: 98%

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Takahashi

Hayashi

Tominari

et al. 2003

Journal of Biological Chemistry

185

189

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic A␤42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of ␥-secretase for A␤42 generation (␥ 42 -secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on ␥-secretase and preferentially inhibits the ␥ 42 -secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro ␥-secretase assay using recombinant amyloid ␤ precursor protein C100 as a substrate. SSide also inhibits activities for the generation of A␤40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for ␥ 42 -secretase in vitro. Our data suggest that SSide is a direct inhibitor of ␥-secretase that preferentially affects the ␥ 42 -secretase activity. Alzheimer's disease (AD)1 is a dementing neurodegenerative disorder of the elderly characterized pathologically by neuronal loss in the cerebral cortex accompanied by massive deposition of amyloid ␤ peptides (A␤) as senile plaques (1). A␤ is produced by sequential proteolytic cleavages of the amyloid ␤ precursor protein (␤APP) by a set of membrane-bound proteases termed ␤-and ␥-secretases. The C-terminal length of A␤ generated by ␥-secretase is heterogeneous; A␤42 is a relatively minor molecular species of the A␤ secreted from cells, but it has a much higher propensity to aggregate and form amyloid compared with other A␤ species. These findings provide strong support for the hypothesis that the deposition of A␤42 is closely related to the pathogenesis of AD, implicating ␥-secretase as an important therapeutic target.Mutations in PS1 or PS2 genes account for the majority of early onset familial AD, and these mutations cause an increase in the ratio or levels of production of A␤42 (1). It is known that PS is essential for the ␥-secretase-mediated intramembranous cleavage not only for ␤APP but for other type I transmembrane proteins (e.g. Notch, ErbB4, E-cadherin, low density lipoprotein receptor-related protein, and CD44) (2). PS proteins undergo endoproteolysis to generate N-and C-terminal fragments and interact with other proteins (i.e. nicastrin, APH-1, and PEN-2) to form a high molecular weight (HMW) protein complex (3). The functional role of PS complex in ␥-secretase activity still remains unknown. However, aspartyl protease transition state analogue inhibitors of ␥-secretase, which harbors a hydroxyl ethylene isostere or a difluoro alcohol moiety, directly label PS fragments (4 -6). In addition, a systematic analysis using a variety of PS mutants revealed that HMW complex formation of PS as well as conserved aspartyl residues within the transmembrane domain are es...

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“…Although some conventional ␥-secretase inhibitors preferentially inhibit A␤40, and can increase A␤42 production under conditions where A␤40 is partially inhibited (24,(53)(54)(55), the subtle switch in A␤ C-terminal cleavage induced by A␤42-lowering NSAIDs to favor shorter A␤ peptides is not seen with any of the published ␥-secretase inhibitors. Nevertheless, we found in this study that these NSAIDs exhibit features that are in common with previously described ␥-secretase inhibitors in 4.…”

Section: Discussionmentioning

confidence: 99%

Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid β42 Production by Direct Modulation of γ-Secretase Activity

Weggen

Eriksen

Sagi

et al. 2003

Journal of Biological Chemistry

274

234

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Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of developing Alzheimer's disease. Recent evidence indicates that some NSAIDs specifically inhibit secretion of the amyloidogenic A␤42 peptide in cultured cells and mouse models of Alzheimer's disease. The reduction of A␤42 peptides is not mediated by inhibition of cyclooxygenases (COX) but the molecular mechanism underlying this novel activity of NSAIDs has not been further defined. We now demonstrate that NSAIDs efficiently reduce the intracellular pool of A␤42 in cell-based studies and selectively decrease A␤42 production in a cell-free assay of ␥-secretase activity. Moreover, we find that presenilin-1 (PS1) mutations, which affect ␥-secretase activity, differentially modulate the cellular A␤42 response to NSAID treatment. Overexpression of the PS1-M146L mutation enhances the cellular drug response to A␤42 lowering NSAIDs as compared with cells expressing wildtype PS1. In contrast, expression of the PS1-⌬Exon9 mutation strongly diminishes the A␤42 response, showing that PS1 mutations can modulate the cellular drug response to NSAID treatment both positively and negatively. Enhancement of the NSAID drug response was also observed with overexpression of the APP V717F mutation but not with Swedish mutant APP, which affects ␤-secretase cleavage. In sum, these results strongly suggest that NSAIDs represent a founding group of compounds that lower A␤42 production by direct modulation of ␥-secretase activity or its substrate.Despite considerable advances in the understanding of Alzheimer's disease (AD) 1 pathology, therapeutic interventions that may halt or reverse the underlying disease process are not available (1, 2). Numerous epidemiological studies support the finding that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs) can decrease the risk for AD by more than 50% (3-6). This protective effect of NSAIDs has generally been ascribed to a diminution of deleterious inflammatory processes in the AD brain (3). However, recent findings suggest a direct impact of some NSAIDs on the amyloid pathology in AD. Treatment of various cultured cells with the NSAIDs sulindac sulfide, ibuprofen, indomethacin, and flurbiprofen specifically inhibited the release of the amyloidogenic A␤42 peptide (7,8). A␤42 is a proteolytic fragment derived from the ␤-amyloid precursor protein (APP) by ␤-and subsequent ␥-secretase cleavage activities and is believed to play a central role in AD pathology (9, 10). Short term administration of ibuprofen to APP transgenic mice lowered brain levels of A␤42 and chronic high dose ibuprofen treatment significantly reduced amyloid plaque numbers and plaque-associated pathology in aging APP transgenic mice (7, 11). The reduction in A␤42 levels was achieved without affecting other APP processing pathways, like secretion of the soluble APP ectodomain (APPs), and is not the result of enhanced degradation or cell-mediated clearance of A␤42. Importantly, within the concentration range tested, A␤42-lower...

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

Cited by 45 publications

References 40 publications

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

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

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid β42 Production by Direct Modulation of γ-Secretase Activity

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