Contribution of the Proteasome to the α-Secretase Pathway in Alzheimer’s Disease
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 catabolites1,2. 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 neuropathology3,4. 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 repair5,6 but could also fulfill both cytoprotective and neurotrophic cell functions7–9. 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 production10–13. 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.
KeywordsSenile Plaque HK293 Cell Baculoviral Vector Human Kidney Cell Alternative Cleavage
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