Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles
Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles
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DOI：
10.1093/brain/awt273
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发表时间：
2013-12-01
期刊：
影响因子：
14.5
通讯作者：
Lent, Roberto
中科院分区：
文献类型：
--
作者：
Andrade-Moraes, Carlos Humberto;Oliveira-Pinto, Ana V.;Lent, Roberto
阿尔茨海默病是老年人痴呆症最常见的原因，但其病理决定因素仍存在争议。淀粉样β蛋白斑块和神经原纤维缠结被直接作为神经功能的干扰物，或间接地通过诱发神经元死亡而导致神经元数量的减少。或者，最初的认知能力下降归因于淀粉样β寡聚体引起的微妙的细胞内事件，导致大规模突触功能障碍后的痴呆，随后是神经元退化和死亡。为了研究阿尔茨海默病是否与老化大脑的绝对细胞数量的变化有关，我们使用了各向同性分割器，这是一种旨在确定大脑区域绝对细胞组成的新技术。我们调查了斑块和缠结是否与神经元丢失有关，或者是否是痴呆症与绝对细胞成分的变化有关，方法是比较严重痴呆患者和无症状个体大脑中的细胞数量-两组都被组织病理学诊断为阿尔茨海默氏症-以及没有疾病病理迹象的正常受试者。我们发现阿尔茨海默病痴呆症患者的海马体和大脑皮层中的神经元数量显著减少，但在无症状的阿尔茨海默病患者中则没有。我们得出结论，神经元丢失与痴呆症有关，而与斑块和缠结的存在无关，这可能解释了为什么具有阿尔茨海默病组织病理学特征的受试者可能没有症状；并排除了淀粉样β沉积是大脑中神经元数量减少的原因。我们发现与无症状的阿尔茨海默病患者和对照组相比，阿尔茨海默病患者大脑皮层和皮质下白质中的非神经细胞数量增加，这表明前者的反应性胶质细胞反应可能与他们所呈现的症状有关。
Alzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-beta plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-beta oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer's disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimer's-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer's disease, but not in asymptomatic subjects with Alzheimer's disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer's disease can be asymptomatic; and exclude amyloid-beta deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer's disease when compared with asymptomatic subjects with Alzheimer's disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present.