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 α-secretase 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 detergent-insoluble, 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.
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Hooper, N.M., Trew, A.J., Parkin, E.T., Turner, A.J. (2002). The Role of Proteolysis in Alzheimer’s Disease. In: Langner, J., Ansorge, S. (eds) Cellular Peptidases in Immune Functions and Diseases 2. Advances in Experimental Medicine and Biology, vol 477. Springer, Boston, MA. https://doi.org/10.1007/0-306-46826-3_39
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