近日，刊登在国际著名杂志Brain上的一篇研究论文中，来自美国西北大学的研究人员通过研究首次在20岁的年轻人大脑中的神经元中发现了淀粉样蛋白的积累，淀粉样蛋白是一种积累在大脑中的异常蛋白，其也是阿尔兹海默氏症发病的主要标志。

　　研究者认为，这项研究首次揭示了在年轻人的大脑中也会存在淀粉样蛋白的积累，而科学界长期以来一直认为这种蛋白仅会在老年人或阿尔兹海默氏症患者大脑神经元的外部进行积累；研究者Changiz Geula教授说道，我们在年轻人大脑中发现淀粉样蛋白的存在让我们感觉非常震惊，而淀粉样蛋白在大脑中积累时间长了会严重影响个体的机体健康。

　　这项研究中研究人员检测了个体基底前脑的胆碱能神经元来帮助理解为何这些神经元会在早期被损伤而且为何在老年人和阿尔兹海默氏症患者机体中也是第一个死亡的神经元，这些神经元主要参与记忆力和注意力的发育；文章中研究者对三组已故的个体进行这些胆碱能神经元的检测，这三组个体分别为年龄在20至66岁的13名认知正常的个体；年龄在70至99岁的16名非痴呆症老年个体以及年龄在60至95岁的21名患阿尔兹海默氏症的老年个体。

　　研究者发现淀粉样蛋白分子在这些个体的年轻时代就开始在大脑的神经元中开始积累了，而且会伴随其一生不断积累存在，而大脑中其它区域的神经细胞并不会表现出相同的淀粉样蛋白的积累，神经元中的淀粉样蛋白会形成小型的毒性团聚物，即淀粉样蛋白多聚体，其就存在于20岁左右的年轻个体的大脑中。

　　Geula表示，问题的关键在于为何这些神经元会早死，淀粉样蛋白形成小型多聚体或许就是关键点，神经元中淀粉样蛋白的积累有可能会引发这些细胞对病理学突变变得易感，进而促进神经元早死；而不断积累状态的淀粉样蛋白多聚体也会对神经元形成损伤并且最终杀死神经元；淀粉样蛋白团聚物会通过向细胞外分泌淀粉样蛋白来促进神经元损伤，从而在阿尔兹海默氏症患者机体中形成大量的淀粉样斑块；最后研究人员希望后期可以进行更为深入的研究来揭示神经元内部的淀粉样蛋白诱发神经元损伤的分子机理，从而为开发新型疗法提供希望。

　　doi:10.1093/brain/awv024
PMC:
PMID:

　　Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease

　　Alaina Baker-Nigh , Shahrooz Vahedi , Elena Goetz Davis , Sandra Weintraub , Eileen H. Bigio , William L. Klein , Changiz Geula

　　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-β 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-β1–42 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-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β 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-β42 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-β 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-β 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.