Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer’s disease (AD) mouse model and is increased at early stage in sporadic AD brain

Autor: Audrey Valverde, Julie Dunys, Thomas Lorivel, Delphine Debayle, Anne-Sophie Gay, Sandra Lacas-Gervais, Bernard. P. Roques, Mounia Chami, Frédéric Checler
Přispěvatelé: Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Excellence Laboratory LabEx DISTALZ, CCMA - Centre Commun de Microscopie Appliquée, Université Nice Côte D'Azur, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Genetically modified mouse
Dendritic spine
[SDV]Life Sciences [q-bio]
Senile plaques
Mice
Transgenic
Plaque
Amyloid
Hippocampal formation
Biology
Glutamyl Aminopeptidase
Hippocampus
Dendritic spines
Pathology and Forensic Medicine
Cell Line
Small hairpin RNA
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
PE3-42Aβ
0302 clinical medicine
Alzheimer Disease
medicine
Animals
Humans
Transgenic mice
Cognitive Dysfunction
Aminopeptidase A
030304 developmental biology
0303 health sciences
Original Paper
Behavior
Amyloid beta-Peptides
Inhibitors
Glutamate receptor
Brain
Exopeptidase
medicine.disease
Cell biology
Mice
Inbred C57BL
Disease Models
Animal
biology.protein
ShRNA
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Neurology (clinical)
N-terminally-truncated Aβ
Alzheimer's disease
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica
Acta Neuropathologica, Springer Verlag, 2021, 141 (6), pp.823-839. ⟨10.1007/s00401-021-02308-0⟩
ISSN: 0001-6322
1432-0533
Popis: One of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ is toxic, prone to aggregation and serves as a seed of Aβ aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aβ and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aβ1-40 to yield Aβ2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aβ-precursor protein (βAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aβ- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aβ-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02308-0.
Databáze: OpenAIRE
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