Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease
Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease
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DOI：
10.1093/brain/awv024
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发表时间：
2015-06-01
期刊：
影响因子：
14.5
通讯作者：
Geula, Changiz
中科院分区：
文献类型：
--
作者：
Baker-Nigh, Alaina;Vahedi, Shahrooz;Geula, Changiz
在神经退行性疾病如阿尔茨海默病中，导致大细胞基底前脑胆碱能神经元选择性脆弱性的机制尚未完全了解。由于年龄是阿尔茨海默病的主要危险因素，因此感兴趣的机制必须包括蛋白质表达、细胞类型特异性标记物和病理学中与年龄相关的改变。本研究探讨了神经元内淀粉样蛋白β积累的程度和特点，特别是纤维形成的42-氨基酸亚型，基底前脑胆碱能神经元在正常的年轻人，正常老年人和阿尔茨海默病的大脑作为一个潜在的贡献者，这些神经元的选择性脆弱性，使用免疫组织化学和蛋白质印迹分析。在整个胆碱能神经元群体中观察到淀粉样蛋白-β（1-42）免疫反应性，而与年龄或阿尔茨海默病诊断无关。这种积累的幅度所揭示的光密度的措施是显着大于皮质锥体神经元，在苍白球和大细胞神经元没有表现出类似程度的淀粉样蛋白免疫反应。用一组β淀粉样蛋白抗体进行的免疫印迹分析证实了在成年早期基底前脑中高浓度的β淀粉样蛋白的积累。在该区域内，总淀粉样β蛋白含量没有与年龄或阿尔茨海默病相关的变化。与此相反，在大分子量的可溶性低聚物物种的增加，观察到与一个高度寡聚体特异性抗体在老年人和阿尔茨海默氏症的大脑相比，年轻的。类似地，使用两种淀粉样蛋白-β（42）抗体，与年轻人相比，中等分子量寡聚物种类在老年人和阿尔茨海默氏症脑中显示出增加。与皮质匀浆相比，小分子量寡聚物种类较低，中间种类在衰老和阿尔茨海默病的基底前脑中富集。区域和年龄相关的差异积累的淀粉样蛋白前体蛋白的表达的改变的结果，证实了免疫染色和蛋白质印迹。我们的研究结果表明，β-淀粉样蛋白的神经元内积累是一个相对选择性的特征，基底前脑胆碱能神经元在成年早期，和增加的流行率的中间和大型低聚体组装状态与衰老和阿尔茨海默病。成年期选择性神经元内β淀粉样蛋白积聚和衰老过程中的寡聚化是阿尔茨海默病基底前脑胆碱能神经元变性的潜在因素。
The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-beta accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-beta(1-42) immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-beta antibodies confirmed accumulation of high concentration of amyloid-beta in basal forebrain early in adult life. There was no age-or Alzheimer-related alteration in total amyloid-beta content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-beta(42) antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-beta accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer's disease. Selective intraneuronal amyloid-beta accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease.