APP processing enzymes (secretases) as therapeutic targets: insights from the use of transgenics (Tgs) and transfected cells.
Secretases degrade amyloid precursor protein (APP) releasing fragments (beta-peptides A beta, A beta x) that assemble to form hallmark extracellular deposits in Alzheimer's disease (AD) correlating with disease severity. As such, secretases supply targets for therapeutic intervention and form the focus of this overview. Progress in elucidating secretases and their modes of catalysis come from exploiting the use of transgenics or transfected cells. In addition to A beta x, secretases also release C-terminal fragments with putative signaling properties (amyloid intracellular domain, AICD) similar in concept to those available for conversion of the Notch-r to release the nuclear transactivator NICD. The review considers lingering questions on APP fragmentation by secretase action, ancillary proteins such as presenilins (PS1/2), nicastrin, XII, or proteases (caspases), and the influence of familial mutations (mAPP, mPS) in terms of fibrillogenesis.
Marks
Neville
N
Division of Neurochemistry, New York University Medical Center, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA. marks@nki.rfmh.org
Berg
Martin J
MJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D051381:Rats; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human