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Cathepsin B degrades amyloid-β in mice expressing wild-type human amyloid precursor protein.

TitleCathepsin B degrades amyloid-β in mice expressing wild-type human amyloid precursor protein.
Publication TypeJournal Article
Year of Publication2012
AuthorsWang C, Sun B, Zhou Y, Grubb A, Gan L
JournalJ Biol Chem
Volume287
Issue47
Pagination39834-41
Date Published2012 Nov 16
ISSN1083-351X
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Cathepsin B, Cystatins, Gene Deletion, Gene Expression, Genetic Diseases, Inborn, Humans, Mice, Mice, Knockout, Mutation, Nerve Tissue Proteins, Neurons, Peptide Fragments, Proteolysis
Abstract

Accumulation of amyloid-β (Aβ), believed to be a key trigger of Alzheimer disease (AD), could result from impaired clearance mechanisms. Previously, we showed that the cysteine protease cathepsin B (CatB) degrades Aβ, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the Aβ-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers Aβ levels by enhancing CatB-mediated Aβ degradation in hAPP(FAD) mice. However, because a vast majority of AD patients do not carry familial mutations, we investigated how the CysC-CatB axis affects Aβ levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total Aβ and Aβ42 levels in hAPP(WT) mice, whereas CatB deletion increased Aβ levels. To determine whether neuron-derived CatB degrades Aβ in vivo, we generated transgenic mice overexpressing CatB under the control of a neuron-specific enolase promoter. Enhancing neuronal CatB activity in hAPP(WT) mice significantly lowered Aβ42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of Aβ42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower Aβ, especially Aβ42, in AD patients with or without familial mutations.

DOI10.1074/jbc.M112.371641
Alternate JournalJ. Biol. Chem.
PubMed ID23024364
PubMed Central IDPMC3501032
Grant ListR01 AG030207 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
CO6 RRO18928 / CO / NCI NIH HHS / United States
R01 AG030207-01A2 / AG / NIA NIH HHS / United States