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Alternative processing of ?-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for ?-secretase dysfunction.

ABSTRACT: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by ?-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor ?-secretase reaction product (A?42) to that of the major reaction product (A?40). Although no PS1 mutations are present, altered A?42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of A?42 as amyloid.Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP ?-secretases and ?-secretases, yielding a fragment that we have named p3-Alc(?) because of the parallel genesis of p3-Alc(?) peptides and the p3 fragment of APP. As with A?, both major and minor p3-Alc(?) s are generated. We studied the alternative processing of p3-Alc(?) in various clinical populations.We previously reported that changes in the A?42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(?) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(?) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(?) variant, p3-Alc(?) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.These results suggest that some SAD may involve alternative processing of multiple ?-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve ?-secretase dysfunction.

SUBMITTER: Hata S

PROVIDER: S-EPMC3306841 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.

Hata Saori S Fujishige Sayaka S Araki Yoichi Y Taniguchi Miyako M Urakami Katsuya K Peskind Elaine E Akatsu Hiroyasu H Araseki Masahiko M Yamamoto Kazuo K Martins Ralph N RN Maeda Masahiro M Nishimura Masaki M Levey Allan A Chung Kathryn A KA Montine Thomas T Leverenz James J Fagan Anne A Goate Alison A Bateman Randall R Holtzman David M DM Yamamoto Tohru T Nakaya Tadashi T Gandy Sam S Suzuki Toshiharu T

Annals of neurology 20110601 6

<h4>Objective</h4>The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observe ...[more]

PMID: 21681798

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Project description:Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta-analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre-registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross-sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50 years were included. For the meta-analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random-effects/fixed-effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92 058 subjects were finally included in the qualitative analysis (71 cross-sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (n = 38) included Asian community-dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (n = 21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta-analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR = 1.58, 95% CI 1.42-1.76) (n = 14), AD (pooled OR = 2.97, 95% CI 2.15-4.08) (n = 3) and non-AD dementia (pooled OR = 1.68, 95% CI 1.09-2.58) (n = 9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta-analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive dysfunction, although further longitudinal research is needed to clarify the causal relationship.

Dataset Information

Alternative processing of ?-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for ?-secretase dysfunction.

Publications

Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.

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