Discipline of Pathology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
The University of Sydney Brain & Mind Centre, Sydney, Australia.
Brain Pathol. 2019 Nov;29(6):726-740. doi: 10.1111/bpa.12717. Epub 2019 Mar 22.
Microglial associations with both the major Alzheimer's disease (AD) pathognomonic entities, β-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 β-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 β-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.
先前对人类组织和小鼠模型的研究都注意到小胶质细胞与阿尔茨海默病（AD）的主要病理特征，β-淀粉样蛋白阳性斑块和 tau 阳性神经原纤维缠结，都有关联。然而，其在 AD 发病机制中的确切作用仍存在争议；主要的工作假说认为，激活的小胶质细胞的促炎活性促进疾病进展。相比之下，其他人则提出，小胶质细胞萎缩和丧失生理及神经保护活性会促进神经退行性变。这项免疫组织化学研究试图通过量化轻度受影响的原发性视觉皮层（PVC）、中度受影响的额上回皮层（SFC）和重度受影响的颞下回皮层（ITC）中 8 例 AD 病例和 15 例年龄和性别匹配、无痴呆的对照者中微胶质细胞的形态亚型，来阐明这一领域。AD 病例在所有区域的β-淀粉样蛋白和 tau 水平均高于对照组。在 SFC 和 ITC 中观察到神经元丢失，并且与后者的萎缩有关。AD 患者 ITC 的一个主要特征是分支（健康）小胶质细胞减少，图像分析证实分支区域和骨骼复杂性减少。激活的小胶质细胞与 AD 无关，但在 AD 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 阳性斑块有关，但占总小胶质细胞群体的比例不到 2%。萎缩性小胶质细胞与 AD 无关，但与脑 pH 呈负相关，这表明濒死事件是这种形态亚型的原因。总的来说，这些新发现表明，在 AD 型病理早期存在小胶质细胞反应，但在 AD 大脑严重受影响的区域，健康小胶质细胞的丢失是突出的特征。
