The presenilins in Alzheimer's disease--proteolysis holds the key.
Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.
Haass
C
C
Adolf-Butenandt-Institute, Department of Biochemistry, Ludwig-Maximilians University Munich, Germany. chaass@pbm.med.uni-muenchen.de
De Strooper
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B
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011480:Protease Inhibitors / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D051880:Receptors, Notch; D015398:Signal Transduction
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D011480:Protease Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human