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

Article type: Research Article

Authors: Wang, Wen-Zhi^{a; 1} | Li, Ming-Wei^{a; 1} | Chen, Ying^{a; 1} | Liu, Li-Yuan^a | Xu, Yong^a | Xia, Zeng-Hui^a | Yu, Yang^{b; c} | Wang, Xiao-Dan^a | Chen, Wei^a | Zhang, Feng^a | Xu, Xiao-Yan^a | Gao, Yong-Feng^a | Zhang, Ji-Guo^{a; *} | Qin, Shu-Cun^{b; c; *} | Wang, Hao^{a; *}

Affiliations: [a] Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, China | [b] Key Laboratory of Atherosclerosis, University of Shandong, Jinan, China | [c] Institute of Artherosclerosis, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, China

Correspondence: [*] Correspondence to: Hao Wang, PhD, Institute of Pharmacology, Shandong First Medical University, Tai’an 271016, Shandong Province, P.R. China. Tel.: +86 0538 6231926; E-mail: [email protected]; Ji-Guo Zhang, PhD, Institute of Pharmacology, Shandong First Medical University, Tai’an 271016, Shandong Province, P.R. China. Tel.: +86 0531 6229753; E-mail: [email protected]; Shu-Cun Qin, MD, PhD, Institute of Atherosclerosis, Shandong First Medical University, Tai’an 271000, Shandong Province, P.R. China. Tel.: +86 0538 6237252; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Alzheimer’s disease, 3×Tg AD mice, GSK3β , PLTP

DOI: 10.3233/JAD-210463

Journal: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1635-1649, 2021