Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 3, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-022-04205-5
Keywords
Meprin beta; Alzheimer's disease; Amyloid precursor protein; Truncated A beta; APP(V717I)
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB877]
- Alzheimer Forschung Initiative e.V.
- Projekt DEAL
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This study reports the generation of a transgenic mouse model of AD lacking the functional Mep1b gene (APP/lon x Mep1b(-/-)). The results showed that when meprin beta is absent, the levels of A beta 1-40 and 1-42 are reduced in APP/lon mice, and the deposition of N-terminally truncated A beta 2-x peptide is also decreased. Importantly, the loss of meprin beta improved cognitive abilities in APP/lon mice.
beta-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described beta-secretase to generate A beta peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative A beta peptides generation is the metalloproteinase meprin beta, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin beta expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon x Mep1b(-/-)). We examined levels of canonical and truncated A beta species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse x Mep1b(-/-). Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. A beta 1-40 and 1-42 levels are reduced in APP/lon mice when meprin beta is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated A beta 2-x peptide deposition is decreased in APP/lon x Mep1b(-/-) mice. Importantly, loss of meprin beta improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin beta within the amyloidogenic pathway and A beta production in vivo.
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