Regulated cleavage of the Alzheimer amyloid precursor protein: molecular and cellular basis.
The relative utilization of alternative processing pathways for APP can be regulated by the activation state of certain protein phosphorylation signal transduction pathways. For example, activation of protein kinase C (PKC), or inactivation of protein phosphatases 1 and 2A, leads to a relative increase in utilization of the nonamyloidogenic, 'alpha-secretase' cleavage pathway for APP processing at the expense of other pathways. The molecular and cellular basis for this regulatory event is unknown. The possible mechanisms of regulated APP cleavage include (either singly or in combination): 1) substrate (ie APP) activation; 2) substrate redistribution; 3) enzyme (ie alpha-secretase) activation; or 4) enzyme redistribution. APP is a phosphoprotein; however, recent evidence from studies of the metabolism of mutant APP molecules suggests that changes in the APP cytoplasmic tail phosphorylation state may not be necessary for the phosphorylation-dependent activation of 'alpha-secretase' cleavage. Further, indirect immunofluorescent studies of the subcellular distribution of APP in the absence or presence of phorbol esters (PKC activators) fail to disclose obvious phorbol-induced redistribution of APP immunoreactivity. Taken together, current data suggest that major candidate phosphorylation-state sensitive targets relevant to the molecular basis of PKC-activated processing (or 'regulated cleavage') of APP include the APP ectodomain as well as secretase enzymes and/or other components of the APP trafficking/processing apparatus. Progress in distinguishing among these possibilities is discussed.
Gandy
S
S
Department of Neurology and Neuroscience, Cornell University Medical College, New York, NY 10021.
Greengard
P
P
D000544:Alzheimer Disease / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D010450:Endopeptidases / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational
D016564:Amyloid beta-Protein Precursor; D010750:Phosphoproteins; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D010450:Endopeptidases