Modelling Sporadic Alzheimer's Disease Using Induced Pluripotent Stem Cells.
Modelling Sporadic Alzheimer's Disease Using Induced Pluripotent Stem Cells.
复制标题
使用诱导的多能干细胞对零星的阿尔茨海默氏病进行建模。
DOI：
10.1007/s11064-018-2663-z
复制
发表时间：
2018-12
影响因子：
4.4
通讯作者：
Kellett KAB
中科院分区：
文献类型：
--
作者：
Rowland HA;Hooper NM;Kellett KAB
开发散发性阿尔茨海默病(SAD)的细胞模型是具有挑战性的，因为疾病发病的起因未知，而且疾病进展缓慢，需要许多年才能在体内发展。人类诱导多能干细胞(IPSCs)的使用彻底改变了建立AD病理模型、研究疾病机制和筛选潜在药物的机会。然而，这项工作的大部分使用了来自家族性AD(FAD)患者的细胞，其中特定的基因突变驱动疾病的发病。虽然这些提供了很好的模型来研究参与神经元毒性并最终导致AD的神经元死亡的下游通路，但它们对推动AD发展的原因和机制提供了很少的洞察。在这篇综述中，我们比较了从FAD和SAD IPSC衍生的细胞系获得的数据，找出了SAD模型中存在的不一致之处，并强调了Aβ清除机制在AD研究中的潜在作用。在IPSC衍生模型中，A DNA清除机制是一个相对研究较少的领域。我们讨论了利用IPSC来源的神经元和神经胶质细胞的共培养和三维培养来开发更具生理学相关性的模型。最后，我们评估我们是否可以开发更好、更一致的模型用于SAD研究，使用IPSCs的遗传分层和识别可用于启动疾病发病的遗传和环境风险因素来模拟SAD。这些考虑为开发更相关的SAD IPSC模型提供了令人兴奋的机会，有助于推动我们对疾病机制的理解，并确定新的治疗靶点。
Developing cellular models of sporadic Alzheimer’s disease (sAD) is challenging due to the unknown initiator of disease onset and the slow disease progression that takes many years to develop in vivo. The use of human induced pluripotent stem cells (iPSCs) has revolutionised the opportunities to model AD pathology, investigate disease mechanisms and screen potential drugs. The majority of this work has, however, used cells derived from patients with familial AD (fAD) where specific genetic mutations drive disease onset. While these provide excellent models to investigate the downstream pathways involved in neuronal toxicity and ultimately neuronal death that leads to AD, they provide little insight into the causes and mechanisms driving the development of sAD. In this review we compare the data obtained from fAD and sAD iPSC-derived cell lines, identify the inconsistencies that exist in sAD models and highlight the potential role of Aβ clearance mechanisms, a relatively under-investigated area in iPSC-derived models, in the study of AD. We discuss the development of more physiologically relevant models using co-culture and three-dimensional culture of iPSC-derived neurons with glial cells. Finally, we evaluate whether we can develop better, more consistent models for sAD research using genetic stratification of iPSCs and identification of genetic and environmental risk factors that could be used to initiate disease onset for modelling sAD. These considerations provide exciting opportunities to develop more relevant iPSC models of sAD which can help drive our understanding of disease mechanisms and identify new therapeutic targets.
登录
查看更多内容
影响因子：
3.6
作者：
Bian A;Neyra JA;Zhan M;Hu MC
通讯作者：
Hu MC
影响因子：
3.3
作者：
Chen M;Lee HK;Moo L;Hanlon E;Stein T;Xia W
通讯作者：
Xia W
影响因子：
12.7
作者：
Arbel-Ornath M;Hudry E;Eikermann-Haerter K;Hou S;Gregory JL;Zhao L;Betensky RA;Frosch MP;Greenberg SM;Bacskai BJ
通讯作者：
Bacskai BJ
影响因子：
15.1
作者：
Duan L;Bhattacharyya BJ;Belmadani A;Pan L;Miller RJ;Kessler JA
通讯作者：
Kessler JA
DOI：
10.18632/aging.100431
发表时间：
2012-02
期刊：
Aging
影响因子：
--
作者：
Cai D;Liu T
通讯作者：
Liu T