Severe white matter astrocytopathy in CADASIL
Severe white matter astrocytopathy in CADASIL
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DOI：
10.1111/bpa.12621
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发表时间：
2018-11-01
期刊：
影响因子：
6.4
通讯作者：
Kalaria, Raj N.
中科院分区：
文献类型：
--
作者：
Hase, Yoshiki;Chen, Aiqing;Kalaria, Raj N.
目的：常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）的特征是MRI上策略性白色物质（WM）高信号。病理特征包括WM变性、小动脉硬化、腔隙性梗死和颗粒状嗜锇物质沉积。基于胶质血管单位受损的假设，我们评估了CADASIL受试者深部WM中星形胶质细胞损伤的性质。方法：我们评估了CADASIL、脑小血管疾病、相似年龄认知正常和老年对照受试者的死后大脑。标准的免疫组织化学，免疫荧光，和公正的体视学方法被用来评估星形胶质细胞，微血管和自噬标记物在五个不同的大脑区域的分布。结果如下：与对照组相比，CADASIL受试者的深层WM总体上显示胶质细胞酸性蛋白（GFAP）阳性的类树突星形胶质细胞数量增加（P=0.037），正常星形胶质细胞百分比减少（P=0.025）。与融合的WM高信号雅阁，前颞极含有丰富的具有移位的水通道蛋白4免疫反应性的树枝状星形胶质细胞。值得注意的是，我们还发现了强有力的证据，免疫定位的自噬标记物，包括微管相关蛋白1，轻链3（LC 3），和隔离体1/p62和Caspase-3在GFAP阳性的clasmatodendritic细胞，特别是在血管周围区域的深部WM。LC 3共定位于90%以上的GFAP阳性的类突胶质细胞中。结论：我们的新发现表明CADASIL中星形胶质细胞经历自噬样细胞死亡，前颞极非常脆弱。我们提出星形胶质细胞从正常的A型转化为肥大的B型，并最终转化为C型细胞。这些观察结果还表明，在CADASIL中，深部WM的胶质血管单位严重受损。
Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. Methods: We evaluated post-mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent, and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels, and autophagy markers in five different brain regions. Results: Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)-positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities, the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalization of autophagy markers including microtubule-associated protein 1, light chain 3 (LC3), and sequestosome 1/p62 and Caspase-3 in GFAP-positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co-localized in more than 90% of the GFAP-positive clasmatodendrocytes. Conclusions: Our novel findings show astrocytes undergo autophagy-like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL.