Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology
Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology
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DOI：
10.1093/brain/awt171
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发表时间：
2013-08-01
期刊：
影响因子：
14.5
通讯作者：
Gomez-Isla, Teresa
中科院分区：
文献类型：
--
作者：
Perez-Nievas, Beatriz G.;Stein, Thor D.;Gomez-Isla, Teresa
临床病理相关性研究和正电子发射断层扫描淀粉样蛋白成像研究表明，一些人可以忍受大量的阿尔茨海默病的病理在他们的大脑没有经历痴呆症。关于这些独特病例的神经病理学表型的细节知之甚少，这些独特病例可能与理解人类对阿尔茨海默病病理学的适应能力有关。我们进行了详细的定量组织病理学和生物化学评估的大脑从非痴呆症的个人死亡前的大脑是免费的实质性阿尔茨海默氏症的病理，非痴呆症的个人死亡前，但其尸检证明显着量的阿尔茨海默氏症的变化（“错配”），和痴呆症的阿尔茨海默氏症的情况。在上级颞沟内衬的多模态联合皮质中进行β淀粉样蛋白斑块负荷的定量、基于体视学的神经元缠结、神经元和反应性胶质细胞的计数以及轴突的形态学分析。测量突触完整性标记物以及可溶性单体和多聚体淀粉样蛋白-β和tau种类的水平。我们的研究结果表明，一些人可以积累与未经历痴呆的阿尔茨海默病患者相同的β淀粉样蛋白斑块和缠结。分析揭示了这两组之间的四个主要表型差异：（i）与痴呆病例相比，错配具有显著的神经元数量、突触标记和轴突几何形状的保留;（ii）与错配相比，痴呆病例具有显著更高的纤维状硫磺素-S-阳性斑块和对符合者特异性抗体NAB 61反应的寡聚淀粉样蛋白-β沉积物的负担;（iii）与对照相比，在痴呆病例中注意到过度磷酸化的可溶性tau多聚体在突触区室中的强烈和选择性积累，但在错配中没有;和（iv）在错配中，痴呆病例中伴随淀粉样蛋白-β和tau病理的强烈神经胶质活化显著减少。进一步的生化测量可溶性淀粉样β-单体，二聚体和更高分子量的寡聚体，在总脑匀浆和突触神经体制剂未能证明之间的显着差异错配和痴呆症的情况下。总之，这些数据表明，淀粉样β蛋白斑块和缠结不一定会导致所有个体的神经系统紊乱和痴呆。我们在脑纤维和可溶性淀粉样蛋白-β和tau累积的概况中以及在区分具有高负荷阿尔茨海默病病理的痴呆和非痴呆个体的神经胶质反应中确定了不同的表型特征。淀粉样蛋白-β以纤维状斑块和密切相关的寡聚淀粉样蛋白-β组装体的形式沉积，位于突触中的过度磷酸化的可溶性tau物质，以及胶质细胞活化在该系列中作为神经毒性和认知改变的可能介质出现，进一步深入了解可能涉及人类对阿尔茨海默病病理变化的易感性或恢复力的因素和途径。
Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-beta plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-beta and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-beta plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-beta deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-beta and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-beta species-monomers, dimers and higher molecular weight oligomers-in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-beta plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-beta and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-beta deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-beta assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.