3×Tg-AD Mice Overexpressing Phospholipid Transfer Protein Improves Cognition Through Decreasing Amyloid-β Production and Tau Hyperphosphorylation

莫里斯水上航行任务 海马体 尼氏体 老年斑 内分泌学 化学 内科学 磷脂转移蛋白 转基因小鼠 免疫印迹 神经退行性变 转基因 阿尔茨海默病 分子生物学 生物 医学 磷脂 病理 生物化学 染色 基因 疾病
作者
Wen-Zhi Wang,Mingwei Li,Ying Chen,Liyuan Liu,Yong Xu,Zeng-Hui Xia,Yang Yu,Xiaodan Wang,Wei Chen,Feng Zhang,Xiaoyan Xu,Yongfeng Gao,Ji-Guo Zhang,Shucun Qin,Hao Wang
出处
期刊:Journal of Alzheimer's Disease [IOS Press]
卷期号:82 (4): 1635-1649 被引量:12
标识
DOI:10.3233/jad-210463
摘要

Background: Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer’s disease (AD); however, the exact effect and mechanism remain unknown. Objective: To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice. Methods: AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain. Results: 3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-β42 (Aβ42) and Aβ40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3β (GSK3β) inactivation via upregulating GSK3β (pSer9). Conclusion: These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aβ production and tau phosphorylation, which is related to GSK3β inactivation.
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