NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus.
Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid beta-protein (A beta), a 40- to 42-amino-acid peptide. The folding of A beta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal-dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C-terminal segments or mutant variants of amyloid precursor protein, the protein from which A beta is derived, exhibit age-dependent spatial memory impairment and attenuated long-term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that A beta disturbs N-methyl-D-aspartic acid (NMDA) receptor-dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that A beta specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca(2+)-dependent protein phosphatase calcineurin, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element-binding protein (CREB). The influence of A beta on each of these downstream effectors of NMDA is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as A beta attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents, are briefly discussed.
Yamin
Ghiam
G
Medical Scientist Training Program (MSTP), David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. gyamin@ucla.edu
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D016194:Receptors, N-Methyl-D-Aspartate