Impaired spatial navigation and age-dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice
Impaired spatial navigation and age-dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice
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DOI：
10.1111/ejn.15835
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发表时间：
2022-10-28
影响因子：
3.4
通讯作者：
ElAli, Ayman
中科院分区：
文献类型：
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作者：
Al-Onaizi, Mohammed;Al-Sarraf, Ahmad;ElAli, Ayman
2型糖尿病（T2 DM）增加了患阿尔茨海默病（AD）的风险，AD被认为是由影响认知功能的异常神经炎症反应驱动的。然而，尚未研究T2 DM对衰老过程中海马功能和突触完整性的影响。在这里，我们研究了衰老在T2 DM AD样病理学的影响，使用瘦素受体缺陷型db/db小鼠模型的T2 DM。我们的研究结果表明，成年T2 DM小鼠在Morris水迷宫（MWM）中表现出受损的空间获取。形态学分析表明，年龄依赖性的齿状回神经元的损失。我们发现，星形胶质细胞密度显着减少，在所有区域的海马在T2 DM小鼠。我们的分析表明，在T2 DM小鼠中，CA 3和海马齿状回的小胶质细胞活化以年龄依赖性方式增加。然而，在成年T2 DM小鼠的海马中，突触前标记蛋白（突触素）和突触后标记蛋白[突触后密度蛋白95（PSD 95）]的表达没有变化。有趣的是，老年T2 DM小鼠海马中突触素和PSD 95表达显著降低，表明海马突触完整性受损。细胞因子谱分析显示，与年轻队列相比，老年T2 DM小鼠海马中存在稳健的促炎细胞因子谱，概述了衰老在糖尿病状态下加重神经炎症谱中的作用。我们的研究结果表明，2型糖尿病损害认知功能，促进神经元的损失，在齿状回和触发海马突触完整性的年龄依赖性恶化，与异常的神经炎症反应。
Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD), which has been proposed to be driven by an abnormal neuroinflammatory response affecting cognitive function. However, the impact of T2DM on hippocampal function and synaptic integrity during aging has not been investigated. Here, we investigated the effects of aging in T2DM on AD-like pathology using the leptin receptor-deficient db/db mouse model of T2DM. Our results indicate that adult T2DM mice exhibited impaired spatial acquisition in the Morris water maze (MWM). Morphological analysis showed an age-dependent neuronal loss in the dentate gyrus. We found that astrocyte density was significantly decreased in all regions of the hippocampus in T2DM mice. Our analysis showed that microglial activation was increased in the CA3 and the dentate gyrus of the hippocampus in an age-dependent manner in T2DM mice. However, the expression of presynaptic marker protein (synaptophysin) and the postsynaptic marker protein [postsynaptic density protein 95 (PSD95)] was unchanged in the hippocampus of adult T2DM mice. Interestingly, synaptophysin and PSD95 expression significantly decreased in the hippocampus of aged T2DM mice, suggesting an impaired hippocampal synaptic integrity. Cytokine profiling analysis displayed a robust pro-inflammatory cytokine profile in the hippocampus of aged T2DM mice compared with the younger cohort, outlining the role of aging in exacerbating the neuroinflammatory profile in the diabetic state. Our results suggest that T2DM impairs cognitive function by promoting neuronal loss in the dentate gyrus and triggering an age-dependent deterioration in hippocampal synaptic integrity, associated with an aberrant neuroinflammatory response.