Dataset Information

Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

ABSTRACT: Beta-amyloid (Abeta) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce Abeta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Abeta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Abeta catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of beta and gamma splice forms of human MMEL were determined in HEK293T cells transduced with the human cDNAs for the two splice forms; this showed degradation of both Abeta(42) and Abeta(40) by hMMEL-beta but not hMMEL-gamma. hMMEL-beta activity was found at the extracellular surface with no significant secreted activity. hMMEL-gamma was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves Abeta near the alpha-secretase site (producing Abeta(1-17)>>Abeta(1-16)). These data establish hMMEL as a mediator of Abeta catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.

SUBMITTER: Huang JY

PROVIDER: S-EPMC2597530 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

Huang J Y JY Bruno A M AM Patel C A CA Huynh A M AM Philibert K D KD Glucksman M J MJ Marr R A RA

Neuroscience 20080516 1

Beta-amyloid (Abeta) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce Abeta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Abeta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P mus ...[more]

PMID: 18571334

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Project description:Various plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aβ42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET-/plasma-, PET-/plasma+, PET+/plasma-, PET+/plasma+) using Alzheimer's Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET-/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET-/plasma+ showed intermediate changes between PET-/plasma- and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma- represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aβ42/40 than IA-Elc. IA-Elc showed more plasma Aβ42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET-/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.

Project description:Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods We included individuals with a positive (n?=?176: 63?±?7?years, 87 (49%) females) or negative (n?=?76: 61?±?9?years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET?), mild cognitive impairment (26 PET+, 24 PET?), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p?=?0.009 and p?<?0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p?=?0.001 and p?=?0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC?=?88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized ? (s?)?=???0.40 to ??0.26; NfL: range s??=???0.35 to ??0.18; all: p?<?0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range s??=?0.22 – 0.11; all: p?<?0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman’s rho>?0.33, p?<?0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman’s rho?=???0.24, p?=?0.001). Discussion and conclusions Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.

Dataset Information

Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

Publications

Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

Similar Datasets

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