Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives.
beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.
Mattson
M P
MP
Sanders-Brown Research Center on Aging, Lexington, Kentucky, USA.
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009420:Nervous System / Q000187:drug effects; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2; D011499:Protein Processing, Post-Translational; D013569:Synapses / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2