By Takaomi Comings Saido
Beta-secretase M. Citron Alpha-secretases S. Ishiura ADAM 10/alpha secretase and presenilins/gamma secretase in APP processing and notch signaling D. Hartmann Gamma-secretase and presenilin M. Wolfe Biochemistry of gamma-secretase (tentative name) S. Sinha Presenilin and intracellular protein shipping Degradation of Abeta by way of neprilysin T.C. Saido Degradation of Abeta by means of endothelin-converting enzyme C. Eckman Degradation of Abeta by way of insulin-degrading enzyme Lipid raft and Abeta metabolism T. Golde Lipid raft and Abeta accumulation M. Morishima-Kawashima and Y. Ihara Transport-dependent clearance of Abeta B. Zlokovic Abeta vaccination C. Lemere
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Extra info for A-Beta Metabolism and Alzheimer's Disease (Neuroscience Intelligence Unit 7)
Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880):535-539. 37. Kawarabayashi T, Younkin LH, Saido TC et al. Age-dependent changes in brain, cerebrospinal fluid, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 2001; 21:372-381. 38. Saido TC, Iwatsubo T, Mann DMA et al. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(pE), in senile plaques.
Based on the experience with other aspartic protease inhibitors, in particular renin and human immunodeficiency virus (HIV) protease drugs, one can predict that the generation of drug-like β-secretase inhibitors will be difficult and time consuming, but that it will be pursued by many companies, given the size of the AD problem and the limited number of validated alternative AD targets. Controversies and Open Questions Compared to other areas of AD research, the β-secretase field has seen surprisingly little controversy.
The identification of transition-state analogue inhibitors of γ-secretase suggested an aspartyl protease mechanism. Consistent with all these findings, two conserved transmembrane aspartates in presenilin are critical for γ-secretase activity, and active site directed inhibitors of γ-secretase bind directly to presenilin. Moreover, presenilin copurifies with γ-secretase activity through size exclusion and affinity chromatography, and antibodies to presenilin can precipitate γ-secretase activity.
A-Beta Metabolism and Alzheimer's Disease (Neuroscience Intelligence Unit 7) by Takaomi Comings Saido