Contribution of the Proteasome to the α-Secretase Pathway in Alzheimer’s Disease

Abstract

It has been extensively documented that the β-amyloid precursor protein (βAPP) can undergo several proteolytic cleavages by various secretases, the activity of which leads to the production of either physiological or potentially pathological catabolites^1,2. Thus, the concomittant and likely sequential action of β- and γ-secretases ultimately triggers the release of the 39–43 amino-acids long Aβ peptide that corresponds to the main component of the senile plaques invading the cortex in late stages of Alzheimer’s disease neuropathology^3,4. An alternative cleavage ascribed to an α-secretase occurs inside the Aβ sequence, thereby generating a secreted C-terminally truncated fragment, APPα², A dense network of evidences indicates that this catabolite can regulate the activity of serine proteinases involved in blood coagulation and wound repair^5,6 but could also fulfill both cytoprotective and neurotrophic cell functions^7–9. Interestingly, this a-secretase-derived product is generally accompanied by a down regulation of the production of Aβ². Thus, it has been well established that effectors targeting the protein kinase C (PKC) enhance the APPα secretion and concomittantly decrease the Aβ production^10–13. It is therefore of interest to identify α-secretase(s) candidates, the activators of which could ultimately lower the formation of Aβ. Here, we present evidences of a phosphorylation-dependent contribution of the proteasome to the α-secretase pathway in human cells.