Targeting Microglia in Alzheimer’s Disease: Pathogenesis and Potential Therapeutic Strategies

Author:

Sun Zhongqing123,Zhang Xin1ORCID,So Kwok-Fai345,Jiang Wen1ORCID,Chiu Kin235

Affiliation:

1. Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China

2. Department of Ophthalmology, School of Clinical Medicine, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

3. State Key Lab of Brain and Cognitive Sciences, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

4. Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou 510632, China

5. Department of Psychology, The University of Hong Kong, Hong Kong SAR, China

Abstract

Microglia, as resident macrophages in the central nervous system, play a multifunctional role in the pathogenesis of Alzheimer’s disease (AD). Their clustering around amyloid-β (Aβ) deposits is a core pathological feature of AD. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have revealed dynamic changes in microglial phenotypes over time and across different brain regions during aging and AD progression. As AD advances, microglia primarily exhibit impaired phagocytosis of Aβ and tau, along with the release of pro-inflammatory cytokines that damage synapses and neurons. Targeting microglia has emerged as a potential therapeutic approach for AD. Treatment strategies involving microglia can be broadly categorized into two aspects: (1) enhancing microglial function: This involves augmenting their phagocytic ability against Aβ and cellular debris and (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce the neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches for AD treatment have garnered attention. Additionally, natural products show promise in enhancing beneficial effects and suppressing inflammatory responses. Clarifying microglial dynamics, understanding their roles, and exploring novel therapeutic approaches will advance our fight against AD.

Funder

Health and Medical Research Fund, Hong Kong, China

Midstream Research Program for Universities, Hong Kong, China

Xijing Innovation Research Institute Joint Innovation Fund, Xian, China

Publisher

MDPI AG

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