GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-β accumulation and neuroinflammation in middle-aged Shugoshin 1 mice.,Aging Cell

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GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-β accumulation and neuroinflammation in middle-aged Shugoshin 1 mice.
Aging Cell ( IF 8.0 ) Pub Date : 2020-08-28 , DOI: 10.1111/acel.13221
Chinthalapally V Rao ₁ , Mudassir Farooqui ₂ , Avanish Madhavaram ₃ , Yuting Zhang ₁ , Adam S Asch ₄ , Hiroshi Y Yamada ₁

Affiliation

The cerebral amyloid‐β accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late‐onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1^−/+) mouse model, a model for mitotic cohesinopathy‐genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid‐β in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid‐β accumulation was determined as 15‐18 months of age (late middle age) in the Sgo1^−/+ model. The amyloid‐β accumulation was associated with unexpected GSK3α/β inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3‐Arc/Arg3.1 axis and the GSK3‐Wnt axis. As observed in human AD brains, neuroinflammation with IFN‐γ expression occurred with amyloid‐β accumulation and was pronounced in the aged (24‐month‐old) Sgo1^−/+ model mice. AD‐relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and β‐oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle‐aged Sgo1^−/+ brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid‐β accumulation in the Sgo1^−/+ model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.

中文翻译：

GSK3-ARC/Arg3.1 和 GSK3-Wnt 信号轴触发中年 Shugoshin 1 小鼠的淀粉样蛋白 β 积累和神经炎症。

中年开始的大脑淀粉样蛋白 β 积累被认为是迟发性阿尔茨海默病 (LOAD) 发病机制中的关键触发事件。然而，分子机制仍然难以捉摸。Shugoshin 1 (Sgo1 ^-/+ ) 小鼠模型是一种在人类 AD 中以较高比率观察到的有丝分裂粘连蛋白基因组不稳定性模型，显示出老年时大脑中淀粉样蛋白 β 的自发积累。借助该模型，可以预期对 LOAD 发展的分子机制有新的见解。在这项研究中，大脑淀粉样蛋白 β 积累的最初出现被确定为 15-18 个月大（中年晚期）在 Sgo1 ^-/+模型。淀粉样蛋白-β 积累与意外的 GSK3α/β 失活、Wnt 信号激活和 ARC/Arg3.1 积累有关，表明 GSK3-Arc/Arg3.1 轴和 GSK3-Wnt 轴均参与其中。正如在人类 AD 大脑中观察到的那样，IFN-γ 表达的神经炎症与淀粉样蛋白 β 积累一起发生，并且在老年（24 个月大）Sgo1 ^-/+模型小鼠中很明显。AD 相关蛋白质组（氧化应激防御、线粒体能量代谢和 β-氧化和过氧化物酶体）分析表明 (a) 中年 Sgo1 ^-/+大脑中 Pdk1 和 Phb 的早期增加，以及 (b) 32 种蛋白质的错误调节在老年时测试的 130 种蛋白质中。因此，Sgo1 ^-/+中的初始淀粉样蛋白-β 积累模型被认为是由 GSK3 失活和由此产生的 Wnt 激活和 ARC/Arg3.1 积累触发的。该模型显示出类似于人类 LOAD 的特征和受影响的通路，包括神经炎症，证明其作为 LOAD 开发机制和临床前 AD 药物研究和开发的研究工具的潜力。

更新日期：2020-10-23

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