The role of proteolysis in Alzheimer's disease

Abstract

Alzheimer's disease is characterised by the progressive deposition of the 4 kDa β-amyloid peptide (Aβ) in extracellular senile plaques in the brain. Aβ is derived by proteolytic cleavage of the amyloid precursor protein (APP) by various proteinases termed secretases, α-Secretase is inhibited by hydroxamate-based zinc metalloproteinase inhibitors such as batimastat with I50 values in the low micromolar range, and displays many properties in common with the secretase that releases angiotensin converting enzyme. A cell impermeant biotinylated derivative of one such inhibitor completely blocked the release of APP from the surface of neuronal cells, indicating that αsecretase cleaves APP at the cell-surface. A range of hydroxamate-based compounds have been used to distinguish between α-secretase and tumour necrosis factor-α convertase, a member of the ADAMs (a disintegrin and metalloproteinase-like) family of zinc metalloproteinases. Recent data suggests that the presenilins may be aspartyl proteinases with the specificity of γ-secretase. Although APP and the presenilins are present in detergentinsoluble, cholesterol- and glycosphingolipid-rich lipid rafts, they do not behave as typical lipid raft proteins, and thus it is unclear whether these membrane domains are the sites for proteolytic processing of APP.