Synaptic dysfunction and oxidative stress in Alzheimer's disease: emerging mechanisms.
In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.
Forero
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Grupo de Neurociencias, Facultad de Medicina e Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia.
Casadesus
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Perry
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Arboleda
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D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D004249:DNA Damage; D023281:Genomics / Q000379:methods; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D053763:Presenilins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D000091042:Reelin Protein; D015398:Signal Transduction
D000682:Amyloid; D001057:Apolipoproteins E; D053763:Presenilins; D000091042:Reelin Protein; C000717127:RELN protein, human