中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (9): 2706-2726.doi: 10.4103/NRR.NRR-D-23-01681

• 原著:退行性病与再生 • 上一篇    下一篇

跑步运动联合声光嗅觉刺激可改善成年APP/PS1小鼠的神经发生

  

  • 出版日期:2025-09-15 发布日期:2024-12-30

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways

Biao Xiao1 , Chaoyang Chu1 , Zhicheng Lin1 , Tianyuan Fang1 , Yuyu Zhou1 , Chuxia Zhang1 , Jianghui Shan1 , Shiyu Chen1 , Liping Li1, 2, 3, *   

  1. 1 Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China;  2 Ningbo Key Laboratory of Behavioral Neuroscience, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China;  3 Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, Zhejiang Province, China
  • Online:2025-09-15 Published:2024-12-30
  • Contact: Liping Li, PhD, liliping@nbu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82001155 (to LL); the Natural Science Foundation of Zhejiang Province, No. LY23H090004 (to LL); the Natural Science Foundation of Ningbo, No. 2023J068 (to LL); the Fundamental Research Funds for the Provincial Universities of Zhejiang Province, No. SJLY2023008 (to LL); the College Students’ Scientific and Technological Innovation Project (Xin Miao Talent Plan) of Zhejiang Province, No. 2022R405A045 (to CC); the Student Research, Innovation Program (SRIP) of Ningbo University, Nos. 2023SRIP1919 (to CZ), 2023SRIP1938 (to YZ), and the K. C. Wong Magna Fund in Ningbo University.

摘要:

成年神经发生减少与行为异常有关,这已在阿尔茨海默病中得到证实。增强成年神经发生对于对抗阿尔茨海默病的至关重要。然而,诱导成年神经发生的非药物干预仍然有限。单一的非药物干预(如有氧运动、声刺激、光刺激和嗅觉刺激)对阿尔茨海默病神经再生和认知水平的改善作用有限,且多因素联合干预的策略和治疗效果尚未完全阐明。此次实验发现,2-8月龄APP/PS1小鼠成年神经发生虽随着年龄的增长而减少,海马中Aβ积累则逐步增加。APP/PS1小鼠在4月龄时出现淀粉样蛋白沉积,6月龄时再生能力下降,且随着疾病的发展,再生能力进一步下降。对4和6个月APP/PS1小鼠进行为期4周的多因素刺激,包括非自愿跑步(46min/d、10m/min、6d/周)、40Hz声光刺激(1h/d、6d/周)和芳香嗅觉刺激(1h/d、6d/周),发现新生细胞(BrdU+细胞)、未成熟神经元(DCX+细胞)、新生未成熟神经元(BrdU+DCX+细胞)和新生星形胶质细胞(BrdU+GFAP+细胞)的数量显著增加,同时海马中Aβ负荷减少,提示这种多因素刺激可增强APP/PS1小鼠的成年海马神经发生,并改善Aβ神经病理变化。此外,Morris水迷宫、新颖物体识别、强迫游泳和悬尾测试发现,多因素刺激可提高APP/PS1小鼠的认知能力,并减轻其抑郁表现。此外,在停止治疗后,多因素刺激在巩固未成熟神经元方面的功效至少能保持2周。多因素刺激还能上调APP/PS1小鼠海马神经元相关蛋白(NeuN、DCX、PSD-95和SYP)、抗细胞凋亡相关蛋白(Bcl-2和PARP)和自噬相关蛋白(LC3B)水平,并降低细胞凋亡相关蛋白(BAX和caspase-9)水平,这可能与脑源性神经营养因子介导的信号通路和抗氧化通路有关。此外,血清代谢组学结果显示,多因素刺激调节与细胞凋亡、氧化损伤和认知相关的代谢产物。上述结果表明,多因素刺激可能是预防和治疗阿尔茨海默病的一种新的非侵入性策略。

https://orcid.org/0000-0001-6628-2029 (Liping Li)

关键词: 阿尔茨海默病,  非自愿跑步运动,  声刺激,  光刺激,  嗅觉刺激,  成年神经发生,  Aβ沉积,  认知障碍,  抑郁样行为,  血清代谢产物,  细胞凋亡,  大脑,  APP/PS1小鼠

Abstract: A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer’s disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer’s disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2–8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5′-bromo-2′-deoxyuridine–positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5′-bromo-2′-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5′-bromo-2′-deoxyuridine-positive/ glial fibrillary acidic protein–positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis–related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis, oxidative damage, and cognition. Collectively, these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer’s disease.

Key words: acousto-optic stimulation,  adult neurogenesis,  Alzheimer’s disease,  amyloid precursor protein/presenilin 1 mice,  amyloid-beta deposition,   brain,  cell apoptosis,  cognitive impairment,  depression-like behavior,  involuntary treadmill exercise,  olfactory stimulation,  serum metabolites