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

• DOI: 10.1007/s00018-022-04205-5
• Publication Date: 2022-03-02T16:02:56Z
• Authors: 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-...; Claus U. Pietrzik
• Keywords: Male; 610 Medizin; 610; Alzheimer’s disease ; Meprin β ; APP(V717I) ; Amyloid precursor protein ; Truncated Aβ; Mice; 03 medical and health sciences; Alzheimer Disease; 610 Medical sciences; Glial Fibrillary Acidic Protein; Animals; Humans; Learning; Crosses, Genetic; Aged; Mice, Knockout; ddc:610; Memory Disorders; 0303 health sciences; Amyloid beta-Peptides; Brain; Metalloendopeptidases; Disease Models, Animal; Astrocytes; Original Article; Female; Amyloid Precursor Protein Secretases; Peptides; Protein Processing, Post-Translational

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 block BACE1 activity and improve AD symptoms have so far failed. A potential candidate for alternative generation metalloproteinase meprin β, which cleaves APP predominantly at alanine p2 this study we can detect an increased β expression brain. Here, report of transgenic APP/lon mouse model lacking functional Mep1b gene (APP/lon × −/− ). We examined levels canonical truncated species using urea-SDS-PAGE, ELISA immunohistochemistry brains . Additionally, investigated cognitive abilities these mice during Morris water maze task. Aβ1-40 1–42 are reduced when absent. Immunohistochemical staining brain sections revealed that N-terminally Aβ2– x peptide deposition decreased mice. Importantly, loss improved rescued learning behavior impairments These observations indicate important role within amyloidogenic pathway production vivo