Molecular genetics of Alzheimer's disease and aging.
Molecular genetics of Alzheimer's disease and aging.
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发表时间：
2005-07
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通讯作者：
R. Cacabelos;L. Fernández-Novoa;V. Lombardi;Y. Kubota;M. Takeda
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作者：
R. Cacabelos;L. Fernández-Novoa;V. Lombardi;Y. Kubota;M. Takeda
阿尔茨海默病是一种遗传复杂的疾病，与多种遗传缺陷相关，无论是突变还是易感性。虽然可能与加速的随机性驱动的衰老过程相关，但阿尔茨海默病是一种独立的临床实体，其中衰老过程与多模态遗传因子和其他病理状况（即，年龄相关的脑血管恶化）和环境因素（即，营养）。阿尔茨海默病遗传学不能完全解释这种疾病的发病机制。因此，很可能环境因素和/或表观遗传现象也有助于阿尔茨海默病的病理和痴呆的表型表达。阿尔茨海默病的基因组学仍处于起步阶段，但这一领域正在帮助了解这种疾病的新方面，包括遗传流行病学，多因素风险因素，与遗传网络和遗传调控代谢级联相关的致病机制。阿尔茨海默病基因组学也有助于开发药物基因组学研究和预防的新策略。功能基因组学、蛋白质组学、药物基因组学、高通量方法、组合化学和现代生物信息学将大大有助于加速阿尔茨海默病和其他复杂疾病的药物开发。痴呆症的多因素遗传功能障碍包括突变位点（APP，PS1，PS2，TAU）和不同的易感基因座（APOE、α 2 M、α ACT、LRP 1、IL 1 α、TNF、ACE、BACE、BCHE、CST 3、MTHFR、GSK 3 β、NOS 3和许多其他基因）分布在整个人类基因组中，可能在导致神经元过早死亡的共同致病机制中会聚，其中线粒体DNA突变可能导致遗传变异性和异质性增加。在阿尔茨海默氏病中，多种致病事件，包括遗传因素、异常或错误折叠蛋白质的积累、原纤维形成、泛素-蛋白酶体系统功能障碍、兴奋性毒性反应、氧化和亚硝化应激、线粒体损伤、突触失效、改变的金属稳态、轴突和树突转运功能障碍以及伴侣误操作，可能汇聚在致病途径中，导致过早死亡和神经变性。其中一些机制是常见的几种神经退行性疾病，这取决于受影响的基因和特定遗传网络的参与，以及表观遗传因素和环境事件。在一些研究中，许多可能与阿尔茨海默病相关的基因在复制研究中不能被证实为候选基因，这表明方法学问题和基因组复杂性导致了错误的结论。阿尔茨海默病功能基因组学的一种不同方法是将个体遗传信息整合到多基因基因型（单倍型样模型）中，并研究基因型-表型相关性和基因型相关的药物基因组学行为。功能基因组学在阿尔茨海默病中的应用可能是分子诊断和理解与阿尔茨海默病相关的神经变性相关的病理生理机制的合适策略。此外，阿尔茨海默病的药物基因组学可能有助于在未来优化药物开发和治疗，提高疗效和安全性，减少副作用和不必要的费用。
Alzheimer's disease is a genetically complex disorder associated with multiple genetic defects, either mutational or of susceptibility. Although potentially associated with an accelerated stochastically driven aging process, Alzheimer's disease is an independent clinical entity in which the aging process exerts a deleterious effect on brain activity in conjunction with polymodal genetic factors and other pathological conditions (i.e., age-related cerebrovascular deterioration) and environmental factors (i.e., nutrition). Alzheimer's disease genetics does not explain in full the etiopathogenesis of this disease. Therefore, it is likely that environmental factors and/or epigenetic phenomena also contribute to Alzheimer's disease pathology and phenotypic expression of dementia. The genomics of Alzheimer's disease is still in its infancy, but this field is aiding the understanding of novel aspects of this disease, including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically regulated metabolic cascades. Alzheimer's disease genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for Alzheimer's disease and other complex disorders. The multifactorial genetic dysfunction in dementia includes mutational loci (APP, PS1, PS2, TAU) and diverse susceptibility loci (APOE, alpha2M, alphaACT, LRP1, IL1 alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3 beta, NOS3 and many other genes) distributed across the human genome, probably converging in a common pathogenic mechanism that leads to premature neuronal death, in which mitochondrial DNA mutations may contribute to increased genetic variability and heterogeneity. In Alzheimer's disease, multiple pathogenic events, including genetic factors, accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and chaperone misoperation may converge in pathogenic pathways leading to premature death and neurodegeneration. Some of these mechanisms are common to several neurodegenerative disorders, which differ depending upon the gene(s) affected and the involvement of specific genetic networks, together with epigenetic factors and environmental events. Many genes potentially associated with Alzheimer's disease in some studies cannot be confirmed as candidate genes in replication studies, indicating that methodological problems and genomic complexity are leading to erroneous conclusions. A different approach to Alzheimer's disease functional genomics is to integrate individual genetic information in polygenic genotypes (haplotype-like model) and to investigate genotype-phenotype correlations and genotype-related pharmacogenomic behaviors. The application of functional genomics to Alzheimer's disease can be a suitable strategy for molecular diagnosis and for understanding pathophysiological mechanisms associated with Alzheimer's disease-related neurodegeneration. Furthermore, the pharmacogenomics of Alzheimer's disease may contribute in the future to optimize drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.