Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland 1023, New Zealand.
Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; School of Psychology, University of Auckland, Auckland 1023, New Zealand.
Neurobiol Dis. 2024 Aug;198:106554. doi: 10.1016/j.nbd.2024.106554. Epub 2024 Jun 4.
Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP protein expression attributed to the presence of more GFAP expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1 and TMEM119 microglia with somal enlargement. IBA-1, TMEM119, and P2RY12 reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1 cells contained either Ki-67 or PCNA, whereas GFAP astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.
亨廷顿病（HD）是一种神经退行性疾病，严重影响基底神经节和大脑皮层区域。虽然星形胶质细胞增生和小胶质细胞增生都有助于基底神经节病理学，但在人类 HD 大脑皮层中，胶质增生的贡献和潜在驱动胶质活动的因素了解较少。我们的研究旨在通过研究先前有记录显示神经元丢失较轻的颞中回（MTG），确定 HD 中难以识别的胶质增生的细微指标，该研究旨在确定 HD 中难以识别的胶质增生的细微指标，因为基底神经节严重退化。免疫组织化学在包含 29 例 HD 和 35 例神经正常病例的 MTG 石蜡包埋组织微阵列（TMA）上进行，以比较关键星形胶质细胞蛋白（胶质纤维酸性蛋白，GFAP；内向整流钾通道 4.1，Kir4.1；谷氨酸转运蛋白-1，GLT-1；水通道蛋白-4，AQP4）、关键小胶质细胞蛋白（离子钙结合接头蛋白-1，IBA-1；人类白细胞抗原（HLA）-DR；跨膜蛋白 119，TMEM119；嘌呤能受体 P2RY12，P2RY12）和增殖指标（Ki-67；增殖细胞核抗原，PCNA）的免疫反应模式。我们的研究结果表明，GFAP 蛋白表达上调归因于 HD 中存在更多表达 GFAP 的细胞，这与皮质突变亨廷顿蛋白（mHTT）沉积增加有关。相比之下，HD 中的 Kir4.1、GLT-1 和 AQP4 免疫反应水平不变。我们还证明了 IBA-1 和 TMEM119 小胶质细胞数量增加，胞体增大。HD 中还鉴定出 IBA-1、TMEM119 和 P2RY12 反应性小胶质细胞免疫表型，表现为棒状、肥大和营养不良的小胶质细胞。在 HD 病例中，IBA-1 细胞含有 Ki-67 或 PCNA，而 GFAP 星形胶质细胞则缺乏有丝分裂核。这些发现表明皮质小胶质细胞增生可能是由 HD 中的增殖驱动的，支持小胶质细胞增殖作为 HD 病理生理学特征的假说。相比之下，HD 中的星形胶质细胞表现出改变的 GFAP 表达谱，与 mHTT 沉积程度相关。
