BIOM30002 Lecture Notes - Lecture 35: Gamma Secretase, Acetylcholinesterase Inhibitor, Amyloid Beta
Document Summary
Only treatments with symptomatic benefit, such as centrally acting cholinesterase inhibitors, are available at present for alzheimer"s disease. Goal: reduce production/increase degradation of amyloid beta because it is neurotoxic. Alpha secretase (also has other substrates), amyloid degrading enzymes, neuroprotection. Gamma secretase complex: good target because it"s an enzyme. Cleavage pathway of gamma secretase: cleaves app to form beta amyloid. Dose-dependently lowered plasma, csf and brain a in animals and lowered plasma and csf a in humans. Then: two phase ill trials (large cohort) showed semagacestat did not slow alzheimer"s disease progression and caused worsening of clinical measures of cognition and the ability to perform activities of daily living. Non-selective: acts on many other substrates so it might damage other processes. Gamma secretase cleaves app and notch - if notch pathway doesn"t work it can cause cancer. Secretase inhibitors are in early stages of clinical development. The merck drug mk-8931 is going through phase 2/3 (dec 2013)
