Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives

Amyloid precursor protein (β-APP), the source of the fibrillogenic amyloid β-peptide (Aβ) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. β-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones A secreted form of β- APP (sAPPα) 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 sAPPα and modulates the activities of potassium channels. N-methyl-D-aspartate receptors, and the transcription factor NFκB. Additional functions of β- APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of β-APP liberates Aβ, which has a propensity to form amyloid fibrils; Aβ 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 Aβ and/or decreasing levels of neuroprotective sAPPα.