Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Neurobiol Dis. 2019 Dec;132:104589. doi: 10.1016/j.nbd.2019.104589. Epub 2019 Aug 24.
Traditionally regarded to coordinate movement, the cerebellum also exerts non-motor functions including the regulation of cognitive and behavioral processing, suggesting a potential role in neurodegenerative conditions affecting cognition, such as Alzheimer's disease (AD). This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD31/PECAM-1) and mural cells (PDGFRβ, αSMA). Amyloid-β expression (total immunolabel intensity) and load (area of immunolabel) was increased by >4-fold within the AD cerebellum. Purkinje cell counts, ubiquitin and tau immunoreactivity were unchanged in AD. IBA1 expression and load was increased by 91% and 69%, respectively, in AD, with no change in IBA1-positive cell number. IBA1-positive cell process length and branching was reduced by 22% and 41%, respectively, in AD. HLA-DR and GFAP immunoreactivity was unchanged in AD. HLA-DR-positive cell process length and branching was reduced by 33% and 49%, respectively, in AD. Fibronectin expression was increased by 27% in AD. Collagen IV, PDGFRβ and αSMA immunoreactivity was unchanged in AD. The number of CD31-positive vessels was increased by 98% in AD, suggesting the increase in CD31 expression and load in AD is due to greater vessel number. The PDGFRβ/CD31 load ratio was reduced by 59% in AD. These findings provide evidence of molecular changes affecting microglia and the neurovasculature within the AD neocerebellum. These changes, occurring without overt neuropathology, support the hypothesis of microglial and neurovascular dysfunction as drivers of AD, which has implications on the neocerebellar contribution to AD symptomatology and pathophysiology.
传统上认为小脑协调运动，但它也具有非运动功能，包括认知和行为处理的调节，这表明小脑在影响认知的神经退行性疾病（如阿尔茨海默病）中可能发挥作用。本研究旨在使用死后人脑组织微阵列（TMA）研究新小脑的神经病理学和与 AD 相关的分子变化。对 24 例 AD 和 24 例匹配对照病例的新小脑石蜡包埋 TMA 以及 6 例 AD 和 6 例对照的新小脑游离切片进行免疫组织化学染色。比较了对照组和 AD 组的神经病理学标志物（淀粉样β、tau、泛素）、浦肯野细胞（钙结合蛋白）、小胶质细胞（IBA1、HLA-DR）、星形胶质细胞（GFAP）、基底膜相关分子（纤维连接蛋白、IV 型胶原）、内皮细胞（CD31/PECAM-1）和壁细胞（PDGFRβ、αSMA）的免疫反应性。AD 小脑内的淀粉样β表达（总免疫标记强度）和负荷（免疫标记面积）增加了 4 倍以上。AD 中浦肯野细胞计数、泛素和 tau 免疫反应性无变化。AD 中 IBA1 表达和负荷分别增加 91%和 69%，而 IBA1 阳性细胞数量无变化。AD 中小胶质细胞 IBA1 阳性细胞的突起长度和分支分别减少 22%和 41%。AD 中 HLA-DR 和 GFAP 免疫反应性无变化。AD 中小胶质细胞 HLA-DR 阳性细胞的突起长度和分支分别减少 33%和 49%。AD 中纤维连接蛋白表达增加 27%。AD 中 IV 型胶原、PDGFRβ 和 αSMA 免疫反应性无变化。AD 中 CD31 阳性血管数量增加 98%，提示 AD 中 CD31 表达和负荷的增加是由于血管数量增加所致。AD 中小胶质细胞 PDGFRβ/CD31 负荷比减少 59%。这些发现为影响 AD 新小脑小胶质细胞和神经血管的分子变化提供了证据。这些变化发生在没有明显神经病理学的情况下，支持小胶质细胞和神经血管功能障碍作为 AD 驱动因素的假说，这对新小脑对 AD 症状和发病机制的贡献具有重要意义。
