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journal article·2026-01Open access

Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1‐Mediated Astrocytic Phagocytosis

Jingdan Zhang, Yanling He, Pin Yang, Hengchang Zhang, Yueyang Tong, Lingling Jiang, Zehan Li, Meichen Yan, Xiaoheng Li, Qinghu Yang, Jing Yang, Zengqiang Yuan, Jiyan Zhang, Jinbo Cheng

Advanced Science· Volume 13· Issue 3
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Source abstract

Abstract

Abstract Alzheimer's disease (AD) is the most common neurodegenerative disorder. Microglia make significant contributions to neuroinflammation and the progression of AD. However, the regulatory role of microglial activation and the communication between microglia and astrocytes in AD are largely unknown. Here, it is found that Rack1 levels are elevated in microglia of patients with AD and AD model mice. The conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD model mice. Mechanistically, the knockout of Rack1 in microglia decreased the number of microglia while increasing both the numbers and phagocytic activities of astrocytes by upregulating the levels of IGF1. The inhibition of IGF1R blocked microglial Rack1 deficiency‐induced astrocyte proliferation and astrocyte‐mediated phagocytosis both in vitro and in vivo. Collectively, the results demonstrated that microglial Rack1 contributes to AD pathology, at least partially through influencing IGF1‐IGF1R signaling between microglia and astrocytes, thus providing a potential target for AD treatment.
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Research context

OpenAlex topics: Neuroinflammation and Neurodegeneration Mechanisms · Neurogenesis and neuroplasticity mechanisms · Alzheimer's disease research and treatments

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Center on Translational Neuroscience, College of Life & Environmental Science Minzu University of China Beijing 100081 China

The Brain Science Center Beijing Institute of Basic Medical Sciences Beijing 100850 China

School of Basic Medical Sciences Anhui Medical University Hefei 230032 China

Clinical Medicine Department of Medical College Yanbian University Yanji 133002 China

School of Life Science & Research Center for Natural Peptide Drugs, Shaanxi Engineering & Technological Research Centre for Conservation & Utilization of Regional Biological Resources Yanan University Yanan 716000 China

Key Laboratory of Neurology (Hebei Medical University) Ministry of Education Shijiazhuang 050000 China

Department of Neuroimmunology and Antibody Engineering Beijing Institute of Basic Medical Sciences Beijing 100850 China

Beijing Engineering Research Center of Food Environment and Public Health Minzu University of China Beijing 100081 China

Funding

National Natural Science Foundation of China

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