Gurdon Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Sci Transl Med. 2012 Mar 7;4(124):124ra29. doi: 10.1126/scitranslmed.3003771. Epub 2012 Feb 15.
Human cellular models of Alzheimer's disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset AD, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a γ-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.
人类阿尔茨海默病（AD）发病机制的细胞模型将能够研究 AD 中的候选发病机制，并测试和开发新的治疗策略。我们报告了源自唐氏综合征患者诱导多能干细胞（iPS）的皮质神经元中 AD 病理的发展。唐氏综合征（由 21 号染色体三体引起）的成年人会出现早发性 AD，可能是由于 21 号染色体上编码淀粉样前体蛋白（APP）的基因表达增加所致。我们发现，源自 iPS 细胞和唐氏综合征患者胚胎干细胞的皮质神经元在培养中数月内就会发展出 AD 病理，而不是在体内数年。这些皮质神经元处理跨膜 APP 蛋白，导致致病肽片段淀粉样β42（Aβ42）的分泌，形成不溶性细胞内和细胞外淀粉样聚集物。γ-分泌酶抑制剂可阻断 Aβ 肽的产生。最后，在源自唐氏综合征患者的 iPS 细胞衍生的皮质神经元中，发现高度磷酸化的 tau 蛋白定位于神经元的胞体和树突，重现了 AD 发病过程的后期阶段。
