Toward a New Concept of Alzheimer's Disease Models: A Perspective from Neuroinflammation
Toward a New Concept of Alzheimer's Disease Models: A Perspective from Neuroinflammation
复制标题
DOI：
10.3233/jad-179914
复制
发表时间：
2018-01-01
影响因子：
4
通讯作者：
Vitorica, Javier
中科院分区：
文献类型：
--
作者：
Gutierrez, Antonia;Vitorica, Javier
开发出有效治疗阿尔茨海默病的方法持续失败，促使人们更好地了解其致病机制并改进当前的动物模型，以促进临床干预的成功。迄今为止，转基因模型已设计用于重现患者大脑中发现的一种或两种蛋白质损伤、细胞外淀粉样斑块和神经元内神经原纤维缠结。然而，近年来，第三种致病成分在这种疾病的发病和进展中正在增强，即主要由大脑驻留免疫细胞小胶质细胞介导的神经炎症反应。与先天免疫有关的基因被鉴定为发生这种神经退行性疾病的危险因素，这凸显了这一点。我们目前的概念主要源自β-淀粉样蛋白产生模型，该模型显示出强大的小胶质细胞激活，支持这些神经胶质细胞最初的有益作用，随后具有促炎细胞毒性功能。这一观点现在受到人类尸检样本中新出现的数据的挑战。我们最近证明，在 Braak V-VI 个体的海马体中，由磷酸 tau 蛋白驱动的小胶质细胞群存在显着的退行性过程，这可能会损害神经元稳态。应考虑小胶质细胞功能障碍/变性的这种情况，以开发更可靠的该疾病动物模型，并提高其对人类药效测试的预测价值。最后，纠正失调的大脑炎症反应可能是恢复认知功能的一个有希望的途径。
The continuing failure to develop an effective treatment for Alzheimer's disease urges a better understanding of the pathogenic mechanisms and the improvement of current animal models to facilitate success for clinical interventions. The transgenic models have been so far designed to recapitulate one, or both, protein lesions found in the brain of patients, the extracellular amyloid plaques and the intraneuronal neurofibrillary tangles. However, in recent years, a third pathogenic component is gaining strength in the onset and progression of this disease, the neuroinflammatory response mediated primarily by the brain's resident immune cells, microglia. This has been highlighted by the identification of genes involved in innate immunity as risk factors to develop this neurodegenerative disease. Our current concept, mostly derived from amyloid-beta producing models which show a robust microglial activation, supports an initial beneficial role of these glial cells followed by a pro-inflammatory cytotoxic function later on. This view is now challenged by emerging data in human postmortem samples. We have recently demonstrated that in the hippocampus of Braak V-VI individuals there is a prominent degenerative process of the microglial population, driven by phospho-tau, that might compromise neuronal homeostasis. This scenario of microglial dysfunction/degeneration should be taken into account for developing more reliable animal models of this disease and improve their predictive value for human drug efficacy testing. Finally, correcting dysregulated brain inflammatory responses might be a promising avenue to restore cognitive function.