Calcium-regulated signaling pathways: role in amyloid beta-induced synaptic dysfunction.
Amyloid beta (Abeta) peptides have been shown to impair synaptic function, especially long-term synaptic plasticity, in transgenic mouse models of Alzheimer's disease (AD) and in acute hippocampal preparations. In the transgenic mice overexpressing mutant forms of human amyloid precursor protein (APP), the deficits in hippocampal long-term potentiation (LTP) occur prior to synaptic loss and cell death, suggesting early functional changes at these synapses. Recent studies demonstrate that Abeta-induced synaptic dysfunction is linked with altered Ca2+ signaling in hippocampal neurons. While reducing Ca2+ influx through NMDA receptors, Abeta peptides elevate intracellular Ca2+ concentration by enhancing Ca2+ influx from voltage-gated Ca2+ channels or nonselective cation channels, or by stimulating Ca2+ release from intracellular stores. Interestingly, acute application of Abeta or APP overexpression inhibits activity-dependent regulation of several protein kinase pathways that require Ca2+ influx via NMDA receptors for activation, including Ca2+/calmodulin-dependent protein kinase II, protein kinase A, and extracellular regulated kinases (Erk). On the other hand, activation of Ca2+-dependent protein phosphatase 2B (calcineurin) is implicated in Abeta inhibition of LTP. Thus, multiple Ca2+-regulated signaling pathways are involved in the synaptic action of Abeta, and malfunction of these pathways may underlie the synaptic dysfunction in early AD.
Xie
Cui-Wei
CW
Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-1761, USA. cxie@mednet.ucla.edu
D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D002118:Calcium