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

Audrey Valverde (1, 2) , Julie Dunys (1, 2) , Thomas Lorivel (1, 2) , Delphine Debayle (1, 2) , Anne-Sophie Gay (1, 2) , Sandra Lacas-Gervais (3) , Bernard P Roques (4) , Mounia Chami (1, 2) , Frédéric Checler (1, 2)

1 IPMC - Institut de pharmacologie moléculaire et cellulaire
2 Excellence Laboratory LabEx DISTALZ
3 CCMA - Centre Commun de Microscopie Appliquée
4 UTCBS - UM 4 (UMR 8258 / U1267) - Unité de Technologies Chimiques et Biologiques pour la Santé

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.

Mots clés: N-terminally-truncated Aβ; PE3-42Aβ; Aminopeptidase A; Inhibitors; ShRNA; Senile plaques; Dendritic spines; Behavior; Transgenic mice; Alzheimer Disease

Domaines: Sciences du Vivant [q-bio]; Neurosciences [q-bio.NC]

Audrey Valverde, Julie Dunys, Thomas Lorivel, Delphine Debayle, Anne-Sophie Gay, et al.. 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. Acta Neuropathologica, 2021, 141 (6), pp.823-839. ⟨10.1007/s00401-021-02308-0⟩. ⟨hal-03239400⟩