中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2012-2014.doi: 10.4103/1673-5374.308096

• 观点:退行性病与再生 • 上一篇    下一篇

临床前阿尔茨海默病（AD病理学）是如何发生的？基因组不稳定性小鼠模型的见解

  

  • 出版日期:2021-10-15 发布日期:2021-03-19

How would preclinical Alzheimer’s disease (AD pathology) occur? An insight from a genomic instability mouse model

Chinthalapally V. Rao, Hiroshi Y. Yamada#br#   

  1. Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Hiroshi Y. Yamada, PhD, hiroshi-yamada@ouhsc.edu.
  • Supported by:
    Our recent work relevant to this prospective were supported by the Kerley-Cade Chair fund to CVR; and by research funds from the Stephenson Cancer Center and by a Pilot Project Award from the Oklahoma Nathan Shock Center for Excellence in the Basic Biology of Aging to HYY. 

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摘要：

Neural Regen Res：Sgo1-/+ 基因组不稳定性在阿尔茨海默病进展中起关键作用

超过95%的阿尔茨海默病是晚发性的，患者在65岁以后表现出临床认知/行为症状。早发性阿尔茨海默病与淀粉样蛋白代谢（APP，PSEN）直接相关的基因突变有关，晚发性阿尔茨海默病相关的遗传易感性基因很难确定。尽管晚发性阿尔茨海默病的发病机制仍存在争议，但淀粉样β累积（始于中年）被广泛认为是早期阿尔茨海默病病理学的触发事件。来自美国奥克拉荷马大学健康科学中心的 Hiroshi Y. Yamada 博士团队于2008年报道了一种基因组不稳定性小鼠模型（Sgo1-/+），在该模型中，淀粉样β蛋白在老年时积聚在大脑中，没有早发性阿尔茨海默病突变。在一项出现在衰老细胞中的新研究中，Hiroshi Y. Yamada 博士团队得出中年时GSK3失活是触发淀粉样β累积的原因这一结论。GSK3失活似乎通过两种方式影响淀粉样β的生成：（i）通过增加ARC/Arg3.1，Arg3.1可以以活性依赖的方式生成淀粉样β；（ii）通过激活典型Wnt信号并驱动大脑中的细胞周期，从而激活淀粉样β累积周期。Hiroshi Y. Yamada 博士团队的研究支持基因组不稳定性和非整倍体在阿尔茨海默病发展中的关键作用的观点，同时提示GSK3在淀粉样β累积和中年阿尔茨海默病病理发病中的作用，以及小鼠模型用于检测晚发性阿尔茨海默病候选药物的有用性。

相关观点文章发表于《中国神经再生研究（英文版）》杂志2021年10  月  10 期发表。

https://orcid.org/0000-0002-0536-5581 (Hiroshi Y. Yamada)

Abstract: More than 95% of Alzheimer’s disease (AD) is late-onset, in which patients show clinical cognition/behavior symptoms after age 65. Unlike early-onset AD that comes with mutations in genes directly involved in amyloid metabolism (APP, PSEN), genetic predispositions associated with late-onset AD are harder to pinpoint, and their mechanistic links to AD development need further investigation. Although the development mechanism of late-onset AD remains controversial, amyloid-beta accumulation, initiated in middle age, is widely accepted as the triggering event for early AD pathology (Du Bois et al., 2010; Sterling et al., 2011). In 2018, we reported a genomic instability mouse model (Sgo1–/+) in which amyloid-beta accumulates in the brain in old age without early-onset AD mutation (Rao et al., 2018). The identification led us to anticipate that the model may reveal the development mechanism of late-onset AD. In a new study that appeared in Aging Cell (Rao et al., 2020a), we identified GSK3 inactivation in middle age as a cause for triggering the amyloid-beta accumulation. Inactivation of GSK3 appeared to affect amyloid-beta generation in two ways: (i) via increasing ARC/Arg3.1, which can generate amyloid-beta in an activity-dependent manner, and (ii) via activating canonical Wnt signaling and driving the cell cycle in the brain, thus activating the “amyloid-beta accumulation cycle” (Rao et al., 2020b). Since the Sgo1–/+ condition prolongs mitosis, during which amyloid-beta generation and accumulation is facilitated, Sgo1–/+ may be mimicking the aneuploid condition prevalent in patients with mild cognitive impairment (MCI) and AD (Potter et al., 2019). Our studies (a) support the notion of the critical roles of genomic instability and aneuploidy in AD development, (b) suggest a role of GSK3 in the onset of amyloid-beta accumulation and onset of AD pathology in middle age, and (c) suggest the usefulness of the mouse model for testing drug candidates for late-onset AD.