The role of proteolysis in Alzheimer's disease.
Alzheimer's disease is characterised by the progressive deposition of the 4 kDa beta-amyloid peptide (A beta) in extracellular senile plaques in the brain. A beta is derived by proteolytic cleavage of the amyloid precursor protein (APP) by various proteinases termed secretases. alpha-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 alpha-secretase cleaves APP at the cell-surface. A range of hydroxamate-based compounds have been used to distinguish between alpha-secretase and tumour necrosis factor-alpha 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 gamma-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.
Hooper
N M
NM
School of Biochemistry and Molecular Biology, University of Leeds, UK.
Trew
A J
AJ
Parkin
E T
ET
Turner
A J
AJ
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019921:Biotinylation; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; C088670:BB 2116; D006877:Hydroxamic Acids; D008563:Membrane Lipids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; C100342:marimastat; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein