APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease.

衰老是阿尔茨海默病（Alzheimer's disease）等神经退行性疾病的主要危险因素，但目前学界对引发脑结构与功能随龄衰退的具体过程仍知之甚少。本研究结合RNA测序（RNA-seq）与高分辨率组织学分析，证实衰老可引发神经血管结构的显著退变，具体表现为基底膜减少、周细胞丢失以及星形胶质细胞功能异常。神经血管衰退足以引发血管渗漏，且与神经炎症反应增强显著相关，其中包括小胶质细胞/单核细胞中补体成分C1QA的表达上调。值得注意的是，从中年至老年长期坚持有氧运动可阻断上述年龄相关性神经血管衰退，减少C1QA阳性小胶质细胞/单核细胞数量，并提升衰老小鼠的突触可塑性与整体行为能力。伴随年龄相关性神经血管衰退与补体激活的同时，衰老小鼠脑中星形胶质细胞源性载脂蛋白E（APOE）的表达水平显著降低，而该表达下调可被有氧运动所阻断。鉴于APOE在维持神经血管单元功能以及发挥抗炎效应中的重要作用，上述结果提示星形胶质细胞源性APOE、年龄相关性神经血管功能障碍与小胶质细胞/单核细胞激活之间可能存在潜在关联。为验证这一假说，本研究对APOE敲除小鼠从中年至老年进行有氧运动干预，结果显示，与野生型（APOE充足型）小鼠不同，在缺乏APOE的情况下，有氧运动对年龄相关性神经血管衰退或小胶质细胞/单核细胞激活几乎无改善作用。综上，本研究数据表明神经血管结构随龄发生衰退，我们认为该过程与小胶质细胞/单核细胞中的补体激活密切相关。有氧运动可阻断上述病理变化，但在APOE缺失的情况下则无法发挥作用，该发现为理解衰老及阿尔茨海默病等神经退行性疾病中神经血管与神经炎症反应间的复杂互作机制提供了全新研究方向。