Secretases as targets for the treatment of Alzheimer's disease: the prospects.
The amyloid hypothesis is still used to explain the pathogenesis of Alzheimer's disease. Despite all progress made, however, the molecular causes of the amyloid pathology, and of the tau pathology, tend to be ignored in most patients with this disorder (sporadic, late-onset). Mutant genes for amyloid precursor protein (APP) or presenilin cause early-onset familial Alzheimer's disease (<1% of all cases) and have helped to elucidate APP processing and amyloid-peptide formation by alpha, beta, and gamma secretases. Inhibition of production of amyloid peptides by inhibitors of beta and gamma secretases has been suggested as the rational and most specific therapeutic approach. Alternatively, or additionally, the activation of alpha secretase would increase non-amyloidogenic processing of APP. Here we review fundamental, genetic, and clinical arguments on which the therapeutic strategies for design of secretase agonists and antagonists are based, with special attention to physiological model systems to assess the potential of current efforts.
Dewachter
Ilse
I
Experimental Genetics Group, Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium.
Van Leuven
Fred
F
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002462:Cell Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human