Production et catabolisme des peptides amyloïdes dans la maladie d'Alzheimer

Senile plaques that accumulate in cortical and sub-cortical areas of Alzheimer's disease (AD)-affected brains are mainly composed of a set of hydrophobic and aggregated peptides referred to as amyloid β-peptides (Aβ). These peptides derive from the proteolytic processing of a transmembrane precursor, the β-amyloid precursor protein (βAPP) that undergoes subsequent cleavages by β- and γ-secretases, respectively. Another enzyme called α-secretase cleaves βAPP in the middle of its Aβ sequence and thereby, lowers its production. Once produced, Aβ peptides can be cleared off by neuropeptidases, mainly insulin-degrading enzyme and neprilysin, or, alternatively, can be biotransformed upon N-terminal truncation by exopeptidases and subsequent cyclisation of the glutamate in position 3. Here, we will describe the nature of the various proteolytic activities documented above and we will discuss briefly their advantages and drawbacks as putative therapeutic targets in AD.