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.

中文翻译：

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小胶质细胞中的阿尔茨海默病基因：值得研究的风险

尽管表达许多关键风险基因，但小胶质细胞在迟发性阿尔茨海默氏病病理生理学中的作用有些模糊，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（尤其是脂质相关）过程失调，再加上年龄相关的动态反应不灵活。小鼠遗传学和侵略性转基因模型的不足意味着应用当前的病因学研究方法存在严重限制。尽管存在这些缺点，广泛使用的淀粉样变性和 tau 蛋白病模型已被证明在剖析小胶质细胞对 AD 病理生理学的功能反应方面具有无价的价值。最近的一些进展使建模工具更接近人类遗传学，提高了病因学和转化研究的有效性。