Department of Neurology, Memory and Aging Center, University of California, San Francisco, California 94158
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut 06030.
J Neurosci. 2022 Jan 12;42(2):288-298. doi: 10.1523/JNEUROSCI.1483-21.2021. Epub 2021 Nov 22.
Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states. Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.
身体活动与降低痴呆风险有关，但细胞和分子机制尚不清楚。我们将动物和研究中证明身体活动与小胶质细胞平衡之间存在因果关系的研究转化为人类研究。拉什记忆与衰老项目的死者生前完成了活动监测（平均日常活动）和认知评估，并在尸检时进行了神经病理学检查。通过免疫组织化学（抗人 HLA-DP-DQ-DR）和形态（%I 期、II 期或 III 期）分析脑组织中小胶质细胞的激活情况，并检测突触蛋白水平（SNAP-25、突触素、复合蛋白-I、VAMP、突触素、突触结合蛋白-1）。在腹侧尾状核、后壳核、下颞叶（IT）和中额叶回估计形态激活的小胶质细胞比例（PAM）。167 名死者死亡时平均年龄为 90 岁，三分之二无痴呆，60%有病理阿尔茨海默病（AD）。调整年龄、性别、教育程度和运动表现后，身体活动与腹侧尾状核和 IT 中的 PAM 呈负相关。在分别有微梗死或 AD 病理学的成年人中，身体活动与腹侧尾状核或 IT 中的 PAM 之间的关系更为显著。中介分析表明，在分别的模型中，IT 中的 PAM 介导了身体活动与 IT 中突触蛋白之间关系的约 30%（1），以及身体活动与整体认知之间关系的约 30%（2）。然而，中介的大小取决于 AD 病理学，在 AD 负担高的成年人中为>40%，但在 AD 负担低的成年人中为<10%。较低的小胶质细胞激活可能是将身体活动与人类与年龄相关的大脑健康联系起来的途径。身体活动可能通过减少促炎小胶质细胞状态来促进与 AD 相关的突触和认知恢复。身体活动与更好的认知衰老和降低神经退行性疾病风险有关，但将人类行为与大脑联系起来的细胞和分子途径尚不清楚。动物研究表明，增加身体活动会导致小胶质细胞激活减少，相应的突触形成和神经发生增加。我们在生前客观地监测身体活动（基于加速度计的活动监测）和认知表现，并在死后量化大脑组织中的小胶质细胞激活和突触标记物。这些是支持小胶质细胞激活作为身体活动与人类大脑健康相关的生理途径的首批数据。虽然需要更多的干预性工作，但我们认为，身体活动可能是一种可改变的行为，可以用来减轻人类的促炎小胶质细胞状态。
