%0 Journal Article %T 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 %+ Institut de pharmacologie moléculaire et cellulaire (IPMC) %+ Excellence Laboratory LabEx DISTALZ %+ CCMA - Centre Commun de Microscopie Appliquée %+ Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)) %A Valverde, Audrey %A Dunys, Julie %A Lorivel, Thomas %A Debayle, Delphine %A Gay, Anne-Sophie %A Lacas-Gervais, Sandra %A Roques, Bernard, P %A Chami, Mounia %A Checler, Frédéric %< avec comité de lecture %@ 0001-6322 %J Acta Neuropathologica %I Springer Verlag %V 141 %N 6 %P 823-839 %8 2021-06 %D 2021 %R 10.1007/s00401-021-02308-0 %K N-terminally-truncated Aβ %K PE3-42Aβ %K Aminopeptidase A %K Inhibitors %K ShRNA %K Senile plaques %K Dendritic spines %K Behavior %K Transgenic mice %K Alzheimer Disease %Z Life Sciences [q-bio] %Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Journal articles %X 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. %G English %2 https://u-paris.hal.science/hal-03239400/document %2 https://u-paris.hal.science/hal-03239400/file/Valverde2021_Article_AminopeptidaseAContributesToBi.pdf %L hal-03239400 %U https://u-paris.hal.science/hal-03239400 %~ UNICE %~ CNRS %~ INC-CNRS %~ UNIV-COTEDAZUR %~ SORBONNE-UNIVERSITE %~ SU-SCIENCES %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ UP-SANTE %~ TEST-HALCNRS %~ SU-TI %~ UTCBS %~ ALLIANCE-SU %~ IPMC %~ TEST2-HALCNRS