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: Valverde A; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Dunys J; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Lorivel T; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Debayle D; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Gay AS; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Lacas-Gervais S; CCMA-Université Côte d'Azur, Nice, France., Roques BP; Faculté de Pharmacie, Université Paris-Descartes, 75006, Paris, France., Chami M; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France., Checler F; INSERM, CNRS, IPMC, Team Labelled 'Laboratory of Excellence (LABEX) DistAlz', Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France. checler@ipmc.cnrs.fr.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2021 Jun; Vol. 141 (6), pp. 823-839. Date of Electronic Publication: 2021 Apr 21.
DOI: 10.1007/s00401-021-02308-0
Abstrakt: 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.
Databáze: MEDLINE
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