Norvin D, Kim G, Baker-Nigh A, Geula C
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States.
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States.
Neuroscience. 2015 Jul 9;298:102-11. doi: 10.1016/j.neuroscience.2015.04.011. Epub 2015 Apr 11.
Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable to damage and loss in a number of neurodegenerative disorders that afflict the elderly, particularly Alzheimer's disease. The reasons for this selective vulnerability remain poorly understood. Given that intraneuronal accumulation of the amyloid-β peptide (Aβ) has been shown to exert deleterious effects on neurons, we tested potential accumulation of Aβ within BFCN in rhesus monkeys, which like the human display age-related accumulation of this peptide in plaques. The non-isoform-specific Aβ antibodies 1282 and 6E10 and the specific antibodies to 1-40 amino acid isoform of Aβ (Aβ1-40) and 1-42 amino acid isoform of Aβ (Aβ1-42) species were used in immunohistochemical experiments of basal forebrain in young and aged rhesus monkeys. All four antibodies visualized cortical plaques in the same sections in which BFCN were examined, in aged but not in young animals. The basal forebrain region within which the BFCN are localized was virtually free of plaques. Appreciable Aβ immunoreactivity was present within the nucleus basalis of Meynert-cholinergic cell group 4 (nbM-Ch4), the major component of BFCN, with all antibodies used. Quantitation of optical density indicated significant age-related increases in immunoreactivity in nbM-Ch4 neurons with the Aβ1-40 (p<0.002) and 1282 (p<0.03) antibodies. Immunoreactivity for 6E10 displayed a small, non-significant age-related increase in nbM-Ch4 neurons (p>0.05). No age-related changes were detected in Aβ1-42 immunoreactivity in these neurons. Unlike the BFCN, cortical neurons within the same sections were virtually devoid of Aβ immunoreactivity, particularly with isoform-specific antibodies. Both smooth and granular intraneuronal Aβ immunoreactivity, reminiscent of endosomal/lysosomal packaged peptide, were observed within nbM-Ch4 neurons. In some nbM-Ch4 neurons, 1282 immunoreactivity had the appearance of large peptide aggregates. Significant accumulation and age-related increase of Aβ in BFCN is likely to interfere with the normal functioning of these neurons. It remains to be determined if similar accumulation of Aβ occurs in human BFCN.
基底前脑胆碱能神经元（BFCN）在许多困扰老年人的神经退行性疾病，尤其是阿尔茨海默病中，会选择性地易受损伤和丧失。这种选择性易损性的原因仍知之甚少。鉴于已表明淀粉样β肽（Aβ）在神经元内的积累会对神经元产生有害影响，我们在恒河猴中测试了Aβ在BFCN内的潜在积累情况，恒河猴与人类一样，会在斑块中出现与年龄相关的这种肽的积累。非异构体特异性的Aβ抗体1282和6E10以及针对Aβ 1 - 40氨基酸异构体（Aβ1 - 40）和Aβ 1 - 42氨基酸异构体（Aβ1 - 42）的特异性抗体，被用于幼年和老年恒河猴基底前脑的免疫组织化学实验。在检查BFCN的同一切片中，所有这四种抗体在老年动物而非幼年动物中都能使皮质斑块显色。BFCN所在的基底前脑区域实际上没有斑块。在Meynert胆碱能细胞群4（nbM - Ch4），即BFCN的主要组成部分的基底核内，使用的所有抗体都显示出明显的Aβ免疫反应性。光密度定量显示，使用Aβ1 - 40（p<0.002）和1282（p<0.03）抗体时，nbM - Ch4神经元中的免疫反应性随年龄增长显著增加。6E10的免疫反应性在nbM - Ch4神经元中显示出与年龄相关的小幅、不显著增加（p>0.05）。在这些神经元中未检测到Aβ1 - 42免疫反应性与年龄相关的变化。与BFCN不同，同一切片中的皮质神经元几乎没有Aβ免疫反应性，尤其是使用异构体特异性抗体时。在nbM - Ch4神经元内观察到了光滑的和颗粒状的神经元内Aβ免疫反应性，这让人联想到内体/溶酶体包裹的肽。在一些nbM - Ch4神经元中，1282免疫反应性呈现出大的肽聚集体的外观。BFCN中Aβ的显著积累和与年龄相关的增加很可能会干扰这些神经元的正常功能。人类BFCN中是否会发生类似的Aβ积累仍有待确定。
