Alzheimer's genes in microglia: a risk worth investigating.

IF 14.9 1区 医学 Q1 NEUROSCIENCES
Ari Sudwarts, Gopal Thinakaran
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引用次数: 0

Abstract

Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer's disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. We note that impairment to protective phenotypes may include prolonged or insufficient microglial activation, resulting in dysregulated metabolomic (notably lipid-related) processes, compounded by age-related inflexibility in dynamic responses. Insufficiencies of mouse genetics and aggressive transgenic modelling imply severe limitations in applying current methodologies for aetiological investigations. Despite the shortcomings, widely used amyloidosis and tauopathy models of the disease have proven invaluable in dissecting microglial functional responses to AD pathophysiology. Some recent advances have brought modelling tools closer to human genetics, increasing the validity of both aetiological and translational endeavours.

小胶质细胞中的阿尔茨海默氏症基因:值得研究的风险。
尽管表达了许多关键的风险基因,但小胶质细胞在迟发性阿尔茨海默病病理生理中的作用有些模糊,据报道,各种表型要么是有害的,要么是保护性的。在此,我们回顾了临床和动物模型研究的一些关键发现,讨论了小胶质细胞遗传学在介导稳态扰动中的作用。我们注意到,保护性表型的损害可能包括小胶质细胞激活时间延长或不足,导致代谢组学(特别是脂质相关)过程失调,再加上动态反应中与年龄相关的不灵活性。小鼠遗传学和积极的转基因建模的不足意味着在病原学调查中应用当前方法的严重限制。尽管存在缺陷,但广泛使用的淀粉样变和牛头病变模型已被证明在解剖小胶质细胞对阿尔茨海默病病理生理的功能反应方面具有宝贵的价值。最近的一些进展使建模工具更接近人类遗传学,增加了病因学和转化努力的有效性。
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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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