Aminopeptidase A and Dipeptidyl aminopeptidase 4 as putative targets in Alzheimers disease

Several studies indicated that pGlu3-Aï? is toxic, prone to aggregation and serves as a seed of A that aggregates and accumulates in Alzheimer’s disease-affected brain. The cyclisation of the glutamate in position 3 requires prior removal of the A 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 in cells. This data derives from mass-spectrometry analysis as well as genetic depletion (shRNA) and pharmacological blockade by selective inhibitors). We will describe data en obtained by in vitro biochemical approach (mass-spectroscopy analysis), measurements of synaptic density (organotypic slices), Ab load (Elisa) and Ab positive lesions (immunohistochemistry) and behavioral studies (memory defects in transgenic mice). Importantly, we demonstrate that, concomitantly to the occurrence of pGlu3-42- A positive plaques, APA and DPP4 activity are augmented at early Braak stages in sporadic AD brains.

Author(s): Frederic Checler

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