Tanzi R E, Kovacs D M, Kim T W, Moir R D, Guenette S Y, Wasco W
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Neurobiol Dis. 1996;3(3):159-68. doi: 10.1006/nbdi.1996.0016.
Four different genes have now been found to contain AD-associated mutations or polymorphisms. While the pathogenic mutations in the early-onset FAD genes, APP, PS1, and PS2 directly cause AD with nearly 100% penetrance, in a larger subset of AD cases with onset over 60 years (maximally for onset at 61-65 years), inheritance of the APOE4 allele confers increased risk for AD but is not sufficient to cause the disease. Together, these four genes appear to account for approximately 50% of FAD cases. We are actively screening the genome for additional FAD loci by genotyping markers in over 400 FAD nuclear pedigrees and affected sib-pairs (83% late-onset and 17% early-onset). We have recently discovered genetic linkage to a novel FAD locus on chromosome 12 as well as another putative locus on chromosome 3 (unpublished findings). Positional cloning strategies are currently under way to identify these potentially novel FAD genes. A common event which is associated with all of the known FAD genes is the excessive accumulation of the A beta peptide and deposition of beta-amyloid in the brain. Thus, a common pathogenic pathway for AD neuropathogenesis appears to center around the cellular trafficking, maturation, and processing of APP, and the subsequent generation, aggregation, and deposition of A beta (or more specifically, A beta 1-42). APP and presenilin gene mutations most likely act as either gain-of-function or dominant negative gene defects which may ultimately lead to the transport of APP into intracellular compartments that promote the enhanced production of A beta or A beta 1-42. AD patients who carry an APOE4 allele experience increased amyloid burden in their brains compared to APOE4-negative AD cases. Thus, the presence of APOE4 would also appear to lead to abnormal generation, aggregation, or clearance of A beta in the brain A beta, perhaps by working in concert with its neuronal receptor, LRP. While the exact mechanisms by which the known FAD gene changes lead to the onset of AD remain unclear, the available data indicate that novel therapies aimed at curbing the generation, aggregation, and deposition of A beta would appear to carry the greatest potential for the effective treatment of this formidable disease.
目前已发现四种不同的基因含有与阿尔茨海默病（AD）相关的突变或多态性。早发性家族性阿尔茨海默病（FAD）基因APP、PS1和PS2中的致病性突变可直接导致AD，其外显率近100%，而在60岁以上发病的更大比例的AD病例中（最大发病年龄为61 - 65岁），APOE4等位基因的遗传会增加患AD的风险，但不足以引发该病。这四个基因共同作用，似乎约占FAD病例的50%。我们正在通过对400多个FAD核心家系和患病同胞对（83%为晚发性，17%为早发性）中的标记进行基因分型，积极在基因组中筛查其他FAD基因座。我们最近发现了与12号染色体上一个新的FAD基因座以及3号染色体上另一个假定基因座的遗传连锁关系（未发表的研究结果）。目前正在采用定位克隆策略来鉴定这些潜在的新型FAD基因。与所有已知FAD基因相关的一个常见事件是Aβ肽在大脑中过度积累以及β - 淀粉样蛋白沉积。因此，AD神经病理发生的一个常见致病途径似乎围绕着APP的细胞转运、成熟和加工，以及随后Aβ（或更具体地说，Aβ1 - 42）的产生、聚集和沉积。APP和早老素基因突变很可能表现为功能获得性或显性负性基因缺陷，这最终可能导致APP转运至细胞内区室，从而促进Aβ或Aβ1 - 42的产生增加。与携带APOE4阴性的AD患者相比，携带APOE4等位基因的AD患者大脑中的淀粉样蛋白负荷增加。因此，APOE4的存在似乎也会导致大脑中Aβ的异常产生、聚集或清除，这可能是通过与其神经元受体LRP协同作用实现的。虽然已知的FAD基因变化导致AD发病的确切机制尚不清楚，但现有数据表明，旨在抑制Aβ产生、聚集和沉积的新型疗法似乎对有效治疗这种可怕疾病具有最大潜力。
