Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease
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Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease. / Marengo, Liana; Armbrust, Fred; Schoenherr, Caroline; Storck, Steffen E; Schmitt, Ulrich; Zampar, Silvia; Wirths, Oliver; Altmeppen, Hermann; Glatzel, Markus; Kaether, Christoph; Weggen, Sascha; Becker-Pauly, Christoph; Pietrzik, Claus U.
in: CELL MOL LIFE SCI, Jahrgang 79, Nr. 3, 168, 02.03.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease
AU - Marengo, Liana
AU - Armbrust, Fred
AU - Schoenherr, Caroline
AU - Storck, Steffen E
AU - Schmitt, Ulrich
AU - Zampar, Silvia
AU - Wirths, Oliver
AU - Altmeppen, Hermann
AU - Glatzel, Markus
AU - Kaether, Christoph
AU - Weggen, Sascha
AU - Becker-Pauly, Christoph
AU - Pietrzik, Claus U
N1 - © 2022. The Author(s).
PY - 2022/3/2
Y1 - 2022/3/2
N2 - 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.
AB - 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.
KW - Aged
KW - Alzheimer Disease/metabolism
KW - Amyloid Precursor Protein Secretases/metabolism
KW - Amyloid beta-Peptides/metabolism
KW - Animals
KW - Astrocytes/metabolism
KW - Brain/metabolism
KW - Crosses, Genetic
KW - Disease Models, Animal
KW - Female
KW - Glial Fibrillary Acidic Protein/metabolism
KW - Humans
KW - Learning
KW - Male
KW - Memory Disorders/pathology
KW - Metalloendopeptidases/deficiency
KW - Mice, Knockout
KW - Peptides/metabolism
KW - Protein Processing, Post-Translational
U2 - 10.1007/s00018-022-04205-5
DO - 10.1007/s00018-022-04205-5
M3 - SCORING: Journal article
C2 - 35235058
VL - 79
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 3
M1 - 168
ER -