The relationship between the morphological subtypes of microglia and Alzheimer's disease neuropathology
The relationship between the morphological subtypes of microglia and Alzheimer's disease neuropathology
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DOI：
10.1111/bpa.12717
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Sutherland, Greg Trevor
中科院分区：
文献类型：
--
作者：
Paasila, Patrick Jarmo;Davies, Danielle Suzanne;Sutherland, Greg Trevor
小胶质细胞与阿尔茨海默病（AD）的两种主要病理实体，β -淀粉样蛋白阳性斑块和tau阳性神经原纤维缠结的关联，已经在先前的人类组织和小鼠模型的研究中被注意到。然而，它们在阿尔茨海默病发病机制中的确切作用仍存在争议；主要的工作假设是，激活的小胶质细胞的促炎活动有助于疾病的进展。相反，其他人提出小胶质营养不良与生理和神经保护活动的丧失促进神经变性。这项免疫组织化学研究试图通过量化8例AD病例和15例年龄和性别匹配的无痴呆的AD类型病理对照中轻度受病初级视觉皮层（PVC）、中度受病上额叶皮层（SFC）和严重受病下颞叶皮层（ITC）的小胶质细胞形态学亚型来获得这一领域的明确。与所有地区的对照组相比，AD病例的β -淀粉样蛋白和tau蛋白水平均有所增加。在SFC和ITC中观察到神经元丢失，并与后者的萎缩有关。AD患者ITC的一个主要特征是分支（健康）小胶质细胞减少，图像分析证实了树枝化面积和骨骼复杂性的减少。活化的小胶质细胞与阿尔茨海默病无关，但在阿尔茨海默病型病理更严重的非痴呆对照组中增加。小胶质细胞簇偶尔与β -淀粉样蛋白和tau阳性斑块相关，但占小胶质细胞总数的不到2%。营养不良小胶质细胞与阿尔茨海默病无关，但与脑pH呈负相关，表明非甾体事件是造成这种形态亚型的原因。总的来说，这些新发现表明，AD型病理存在早期小胶质细胞反应，但健康小胶质细胞的丧失是AD大脑严重受影响区域的突出特征。
Microglial associations with both the major Alzheimer's disease (AD) pathognomonic entities, beta-amyloid-positive plaques and tau-positive neurofibrillary tangles, have been noted in previous investigations of both human tissue and mouse models. However, the precise nature of their role in the pathogenesis of AD is debated; the major working hypothesis is that pro-inflammatory activities of activated microglia contribute to disease progression. In contrast, others have proposed that microglial dystrophy with a loss of physiological and neuroprotective activities promotes neurodegeneration. This immunohistochemical study sought to gain clarity in this area by quantifying the morphological subtypes of microglia in the mildly-affected primary visual cortex (PVC), the moderately affected superior frontal cortex (SFC) and the severely affected inferior temporal cortex (ITC) of 8 AD cases and 15 age and gender-matched, non-demented controls with ranging AD-type pathology. AD cases had increased beta-amyloid and tau levels compared to controls in all regions. Neuronal loss was observed in the SFC and ITC, and was associated with atrophy in the latter. A major feature of the ITC in AD was a decrease in ramified (healthy) microglia with image analysis confirming reductions in arborized area and skeletal complexity. Activated microglia were not associated with AD but were increased in non-demented controls with greater AD-type pathology. Microglial clusters were occasionally associated with beta-amyloid- and tau-positive plaques but represented less than 2% of the total microglial population. Dystrophic microglia were not associated with AD, but were inversely correlated with brain pH suggesting that agonal events were responsible for this morphological subtype. Overall these novel findings suggest that there is an early microglial reaction to AD-type pathology but a loss of healthy microglia is the prominent feature in severely affected regions of the AD brain.