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慢性睡眠剥夺加重APP/PS1/tau小鼠学习记忆能力和病理损伤

王纯¹, 曹旭², 尹静¹, 高文蕊¹, 李蔚然¹, 祁金顺¹, 武美娜^1,*

¹山西医科大学生理学系，细胞生理学教育部重点实验室，太原 030001；²山西医科大学医学影像学院，太原 030001

摘要

睡眠在认知功能和情绪的调节过程中发挥重要作用。近年研究显示，睡眠障碍是阿尔茨海默病(Alzheimer’s disease, AD)重要的危险因素之一，但慢性睡眠剥夺对于AD模型小鼠认知功能的影响及其机制尚不明确。本研究采用改良多平台法对8月龄雄性APP/PS1/tau三转基因AD模型(3xTg-AD)小鼠和野生型(wild type, WT)小鼠(每组8只)进行连续21天、每天20 h的睡眠剥夺。睡眠剥夺结束后，采用旷场、高架十字迷宫、糖水偏好、物体识别、Y迷宫和条件恐惧记忆实验等多种行为学手段观察慢性睡眠剥夺对3xTg-AD小鼠的焦虑和抑郁样行为以及多种认知功能的影响，并通过免疫组织化学染色观察小鼠海马区β淀粉样蛋白(amyloid β protein, Aβ)斑块沉积、神经原纤维缠结和小胶质细胞的活化程度。结果显示：(1)慢性睡眠剥夺未影响3xTg-AD小鼠的焦虑(P = 0.539)和抑郁样行为(P = 0.874)；(2)慢性睡眠剥夺加重了3xTg-AD小鼠的识别记忆(P < 0.001)、工作记忆(P = 0.002)和条件恐惧记忆能力(P = 0.039)损伤；(3)慢性睡眠剥夺增加了3xTg-AD小鼠海马区Aβ斑块的沉积(P < 0.001)和小胶质细胞的过度活化(P < 0.001)，但并未导致tau蛋白异常磷酸化和神经原纤维缠结出现。以上结果表明，慢性睡眠剥夺加重了3xTg-AD小鼠的识别记忆、工作记忆和条件恐惧记忆能力损伤，且其损伤作用与3xTg-AD小鼠海马区Aβ斑块沉积增加和小胶质细胞过度活化密切相关。

关键词： APP/PS1/tau转基因小鼠; 慢性睡眠剥夺; 学习记忆; β淀粉样蛋白; 小胶质细胞

分类号：R338

Chronic sleep deprivation exacerbates cognitive and pathological impairments in APP/PS1/tau triple transgenic Alzheimer's disease model mice

WANG Chun¹, CAO Xu², YIN Jing¹, GAO Wen-Rui¹, LI Wei-Ran¹, QI Jin-Shun¹, WU Mei-Na^1,*

¹Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan 030001, China；²The School of Imaging Medicine, Shanxi Medical University, Taiyuan 030001, China

Abstract

Sleep exerts important functions in the regulation of cognition and emotion. Recent studies have found that sleep disorder is one of the important risk factors for Alzheimer’s disease (AD), but the effects of chronic sleep deprivation on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1/tau triple transgenic AD model (3xTg-AD) mice and wild type (WT) mice (n = 8 for each group) were subjected to chronic sleep deprivation by using the modified multiple platform method, with 20 h of sleep deprivation each day for 21 days. Then, open field test, elevated plus maze test, sugar water preference test, object recognition test, Y maze test and conditioned fear memory test were performed to evaluate anxiety- and depression-like behaviors, and multiple cognitive functions. In addition, the immunohistochemistry technique was used to observe pathological characteristics in the hippocampus of mice. The results showed that: (1) Chronic sleep deprivation did not affect anxiety- (P = 0.539) and depression-like behaviors (P = 0.874) in 3xTg-AD mice; (2) Chronic sleep deprivation exacerbated the impairments of object recognition memory (P < 0.001), working memory (P = 0.002) and the conditioned fear memory (P = 0.039) in 3xTg-AD mice; (3) Chronic sleep deprivation increased amyloid β (Aβ) deposition (P < 0.001) and microglial activation (P < 0.001) in the hippocampus of 3xTg-AD mice, without inducing abnormal tau phosphorylation and neurofibrillary tangles. These results indicate that chronic sleep deprivation exacerbates the impairments of recognition memory, working memory and conditioned fear memory in 3xTg-AD mice by aggravating Aβ deposition and the excessive activation of microglia in the hippocampus.

Key words: APP/PS1/tau transgenic model mice; chronic sleep deprivation; learning and memory; β amyloid protein; microglia

收稿日期：2020-10-09　　录用日期：2021-03-11

通讯作者：武美娜　　E-mail: wmna@163.com

DOI: 10.13294/j.aps.2021.0032

引用本文：

王纯, 曹旭, 尹静, 高文蕊, 李蔚然, 祁金顺, 武美娜. 慢性睡眠剥夺加重APP/PS1/tau小鼠学习记忆能力和病理损伤[J]. 生理学报 2021; 73 (3): 471-481.

WANG Chun, CAO Xu, YIN Jing, GAO Wen-Rui, LI Wei-Ran, QI Jin-Shun, WU Mei-Na. Chronic sleep deprivation exacerbates cognitive and pathological impairments in APP/PS1/tau triple transgenic Alzheimer's disease model mice. Acta Physiol Sin 2021; 73 (3): 471-481 (in Chinese with English abstract).