Emerging microglial biology highlights potential therapeutic targets for Alzheimer's disease

IF 12.5 1区 医学 Q1 CELL BIOLOGY
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引用次数: 0

Abstract

Alzheimer's disease is a chronic degenerative disease of the central nervous system, which primarily affects elderly people and accounts for 70–80 % of dementia cases. The current prevailing amyloid cascade hypothesis suggests that Alzheimer’s disease begins with the deposition of amyloid β (Aβ) in the brain. Major therapeutic strategies target Aβ production, aggregation, and clearance, although many clinical trials have shown that these therapeutic strategies are not sufficient to completely improve cognitive deficits in AD patients. Recent genome-wide association studies have identified that multiple important regulators are the most significant genetic risk factors for Alzheimer's disease, especially in the innate immune pathways. These genetic risk factors suggest a critical role for microglia, highlighting their therapeutic potential in treating neurodegenerative diseases. In this review, we discuss how these recently documented AD risk genes affect microglial function and AD pathology and how they can be further targeted to regulate microglial states and slow AD progression, especially the highly anticipated APOE and TREM2 targets. We focused on recent findings that modulation of innate and adaptive neuroimmune microenvironment crosstalk reverses cognitive deficits in AD patients. We also considered novel strategies for microglia in AD patients.

新出现的小胶质细胞生物学特性凸显了阿尔茨海默病的潜在治疗靶点。
阿尔茨海默病是一种慢性中枢神经系统变性疾病,主要影响老年人,占痴呆症病例的 70-80%。目前流行的淀粉样蛋白级联假说认为,阿尔茨海默病始于淀粉样蛋白β(Aβ)在大脑中的沉积。主要的治疗策略以 Aβ 的生成、聚集和清除为目标,但许多临床试验表明,这些治疗策略不足以完全改善阿尔茨海默病患者的认知障碍。最近的全基因组关联研究发现,多个重要的调节因子是阿尔茨海默病最重要的遗传风险因素,尤其是在先天性免疫通路中。这些遗传风险因素表明了小胶质细胞的关键作用,凸显了它们在治疗神经退行性疾病方面的治疗潜力。在这篇综述中,我们将讨论这些最近记录在案的痴呆症风险基因如何影响小胶质细胞功能和痴呆症病理,以及如何进一步靶向调节小胶质细胞状态和减缓痴呆症进展,尤其是备受期待的 APOE 和 TREM2 靶点。我们重点研究了最近的发现,即调节先天性和适应性神经免疫微环境串扰可逆转AD患者的认知障碍。我们还考虑了针对注意力缺失症患者小胶质细胞的新策略。
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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