Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK.
Institute for Cell and Molecular Biosciences, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK.
Brain Pathol. 2018 Nov;28(6):832-843. doi: 10.1111/bpa.12621.
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.
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.
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.
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.
脑常染色体显性动脉病伴皮质下梗死和白质脑病（CADASIL）的特征是 MRI 上出现策略性的白质（WM）高信号。病理学特征包括 WM 退化、小动脉粥样硬化、腔隙性梗死和颗粒状亲银物质沉积。基于神经胶质血管单元受损的假说，我们评估了 CADASIL 患者深部 WM 中星形胶质细胞损伤的性质。
我们评估了 CADASIL、脑小血管病、相似年龄认知正常和老年对照受试者的死后大脑。使用标准免疫组织化学、免疫荧光和无偏立体学方法评估了五个不同脑区星形胶质细胞、微血管和自噬标志物的分布。
与对照组相比，CADASIL 患者的深部 WM 总体上表现出更多的胶质纤维酸性蛋白（GFAP）阳性的有树突棘的星形胶质细胞（P=0.037），而正常形态星形胶质细胞的比例减少（P=0.025）。与弥漫性 WM 高信号一致，前颞极含有丰富的有树突棘的星形胶质细胞，伴水通道蛋白 4 免疫反应性移位。值得注意的是，我们还发现了强烈的证据表明自噬标志物包括微管相关蛋白 1、轻链 3（LC3）和自噬相关蛋白 1、轻链 3（LC3）和自噬相关蛋白 1、轻链 3（LC3）和自噬相关蛋白 1、轻链 3（LC3）和自噬相关蛋白 1、轻链 3（LC3）在 GFAP 阳性的有树突棘的星形胶质细胞中免疫定位，特别是在深部 WM 的血管周围区域。LC3 在超过 90%的 GFAP 阳性有树突棘的星形胶质细胞中存在共定位。
我们的新发现表明 CADASIL 中星形胶质细胞发生自噬样细胞死亡，前颞极高度易损。我们提出星形胶质细胞从正常形态的 A 型转变为肥大的 B 型，最终转变为有树突棘的 C 型。这些观察结果还表明 CADASIL 深部 WM 的神经胶质血管单元严重受损。
