中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (10): 2969-2981.doi: 10.4103/NRR.NRR-D-23-01993

• 原著:退行性病与再生 • 上一篇    下一篇

G 蛋白信号调节器6:阿尔茨海默病干预的潜在靶点

  

  • 出版日期:2025-10-15 发布日期:2025-02-09

Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in a mouse model of Alzheimer’s disease

Mackenzie M. Spicer1, 2, 3, Jianqi Yang1, 2, Daniel Fu1 , Alison N. DeVore1 , Marisol Lauffer2, 4, Nilufer S. Atasoy1, 2, Deniz Atasoy1, 2, Rory A. Fisher1, 2, *   

  1. 1 Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA;  2 Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA;  3 Interdisciplinary Graduate Program in Molecular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA;  4 Neural Circuits and Behavior Core, University of Iowa Carver College of Medicine, Iowa City, IA, USA
  • Online:2025-10-15 Published:2025-02-09
  • Contact: Rory A. Fisher, PhD, rory-fisher@uiowa.edu.
  • Supported by:
    This study was supported by the National Institutes of Health, Nos. AA025919, AA025919-03S1, and AA025919-05S1 (all to RAF).

摘要:

海马神经元丧失会导致阿尔茨海默病的认知功能障碍。阿尔茨海默病患者的成年海马神经元生成减少。运动可刺激啮齿类动物的成年海马神经元发生,并改善阿尔茨海默病患者的记忆功能,延缓认知能力减退。然而,运动诱导成体海马神经发生和改善阿尔茨海默病患者认知能力的分子途径尚不清楚。最近,G 蛋白信号调节器 6(RGS6)被确定为主动跑步诱导阿尔茨海默病小鼠成体海马神经发生的介导因子。实验生成了新型 RGS6fl/fl; APPSWE小鼠,并以逆转录病毒方法研究了从齿状回神经元祖细胞中删除RGS6基因对自主跑步诱导的阿尔茨海默病小鼠成年海马神经发生和认知能力的影响。结果发现,APPSWE 小鼠的自主跑步可使其海马认知障碍恢复到基本正常水平;齿状回神经元祖细胞中缺失RGS6会阻止这种认知功能的恢复和成年海马神经发生减少。未运动的APPSWE小鼠的成年海马神经发生减少,RGS6缺失会导致齿状回神经前体细胞的海马神经发生。RGS6在阿尔茨海默病患者的齿状回神经元中表达。总之,G 蛋白信号调节器 6 (RGS6) 介导运动诱导阿尔茨海默病后的海马神经发生、学习和记忆功能恢复,提示海马齿状回神经前体细胞中的RGS6是阿尔茨海默病干预的潜在靶点。

https://orcid.org/0000-0003-3108-4836 (Rory A. Fisher)

Abstract: Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running–induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6fl/fl; APPSWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running–induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model. We found that voluntary running in APPSWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APPSWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running–induced rescue of impaired cognition and adult hippocampal neurogenesis in APPSWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

Key words: adult hippocampal neurogenesis,  , Alzheimer’s disease,  , dentate gyrus,  , exercise,  , learning/memory,  , neural precursor cells,  , regulator of G protein signaling 6 (RGS6)