Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease
Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease
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DOI：
10.1186/s12974-020-01935-w
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发表时间：
2020-09-15
影响因子：
9.3
通讯作者：
Kanninen, Katja M.
中科院分区：
文献类型：
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作者：
Belaya, Irina;Ivanova, Mariia;Kanninen, Katja M.
背景：增加体育锻炼可以改善认知功能，减少与阿尔茨海默病(AD)相关的病理改变。然而，运动对阿尔茨海默病患者特定脑细胞水平的有益影响的机制仍未得到充分研究。星形胶质细胞在AD病理中的作用被广泛描述，但它们在运动介导的神经保护中的确切作用值得进一步研究。在这里，我们研究了长期的自愿体育锻炼对星形胶质细胞状态的调节作用。方法雄性5xFAD小鼠及其野生型窝仔在1.5~7月龄自由使用跑轮。一系列行为测试被用来评估自愿锻炼对认知和学习的影响。通过各种组织学和生化测量来评估神经元丢失、神经再生障碍、β-淀粉样蛋白(Aβ)沉积和炎症。对5xFAD小鼠进行了复杂的形态分析，以描述星形胶质细胞在运动诱导的神经保护中的具体参与。结果长期自愿运动可逆转7月龄5xFAD小鼠的认知功能障碍，但不影响神经发生、神经元丢失、Aβ斑块沉积或小胶质细胞激活。运动增加5xFAD大鼠海马区胶质纤维酸性蛋白(GFAP)免疫反应性和GFAP阳性星形胶质细胞的数量。运动5xFAD组小鼠海马区GFAP阳性星形胶质细胞的初级分支数目和胞体面积均增加。一般来说，与斑块相关的GFAP阳性星形胶质细胞相比，远离Aβ斑块的星形胶质细胞体积更小，突起更简单。GFAP阳性星形胶质细胞的形态改变伴随着星形胶质细胞脑源性神经营养因子(BDNF)的增加和突触后蛋白PSD-95的恢复。结论自愿运动可调节星形胶质细胞的反应性状态，这种调节可能通过星形胶质细胞的BDNF和PSD-95与改善5xFAD海马区的认知功能有关。参与这种调节的分子途径可能成为防治阿尔茨海默病的靶点。
Background Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer's disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. Methods Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (A beta) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. Results Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, A beta plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from A beta plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. Conclusions Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.