Publications

Dernière publication 21/04/2021

Aminopeptidase A contributes to biochemical- anatomical and cognitive defects in

One of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Abeta peptide species harboring a pyroglutamate at...

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    [title] => Aminopeptidase A contributes to biochemical- anatomical and cognitive defects in
    [paragraph] => 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
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Authors
A Valverde, J Dunys, T Lorivel et al

 Lab
Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d’Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France
Journal
Acta Neuropathologica
Abstract
One of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Abeta peptide species harboring a pyroglutamate at position three pE3-Abeta. Several studies indicated that pE3-Abeta is toxic, prone to aggregation and serves as a seed of Abeta 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 Abeta 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 Abeta 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 Abeta1-40 to yield Abeta2-40. 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 Abeta-precursor protein (betaAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Abeta- and Abeta1-42-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 pE3-42Abeta-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 Abeta N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.
BIOSEB Instruments Used
Rotarod (BX-ROD),Aron Test or Four Plates Test (LE830)

Keywords/Topics
Maladie d'Alzheimer
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