Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease

  • Liana Marengo
  • Fred Armbrust
  • Caroline Schoenherr
  • Steffen E Storck
  • Ulrich Schmitt
  • Silvia Zampar
  • Oliver Wirths
  • Hermann Altmeppen
  • Markus Glatzel
  • Christoph Kaether
  • Sascha Weggen
  • Christoph Becker-Pauly
  • Claus U Pietrzik

Related Research units

Abstract

β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described β-secretase to generate Aβ 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 Aβ peptides generation is the metalloproteinase meprin β, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin β 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 × Mep1b-/-). We examined levels of canonical and truncated Aβ species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b-/-. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aβ1-40 and 1-42 levels are reduced in APP/lon mice when meprin β is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aβ2-x peptide deposition is decreased in APP/lon × Mep1b-/- mice. Importantly, loss of meprin β improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin β within the amyloidogenic pathway and Aβ production in vivo.

Bibliographical data

Original languageEnglish
Article number168
ISSN1420-682X
DOIs
Publication statusPublished - 02.03.2022

Comment Deanary

© 2022. The Author(s).

PubMed 35235058