Abstract Body

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 in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. We have identified aminopeptidase A (APA)and dipeptidyl peptidase 4 (DDD4) as the main exopeptidases involved in an additional manner. First, we show by mass-spectrometry that human recombinant APA and DPP4 truncate synthetic Aβ1-40 to yield Aβ2-40 and Aβ3-40, respectively. We demonstrate that the pharmacological blockade of APA and DPP4 with theirs selective inhibitors RB150 and sitagliptin 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 enzymes activities and lowering of their expression by shRNA affect Aβ pE3-42- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA and DPP4 inhibitors and specific shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of Aβ pE3-42-positive plaques, APA and DPP4 activity are augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA and DPP4 are two key exopeptidases involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with Aβ-related AD pathology.