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

One of the main components of senile plaques in Alzheimer's disease (AD)-affected brain is the A beta peptide species harboring a pyroglutamate at position three pE3-A beta. Several studies indicated that pE3-A beta is toxic, prone to aggregation and serves as a seed of A beta 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 A beta 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 A beta 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 A beta 1-40 to yield A beta 2-40. 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 A beta-precursor protein (beta APP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42A beta- and A beta 1-42-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 pE3-42A beta-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 A beta N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.