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Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic
Jingdan Zhang1,2, Yanling He3, Pin Yang3
1Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, 100081, China.
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.
Insights
Rack1 in microglia drives Alzheimer's disease (AD) progression by promoting neuroinflammation and Aβ aggregation. Targeting microglial Rack1 and its influence on astrocyte signaling offers a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is a leading neurodegenerative disorder.
- Microglia are key players in AD-associated neuroinflammation and disease progression.
- The precise roles of microglial activation and microglia-astrocyte communication in AD remain unclear.
Purpose of the Study:
- To investigate the role of Rack1 in microglia during Alzheimer's disease.
- To elucidate the mechanisms by which microglial Rack1 influences AD pathology.
- To explore Rack1 as a potential therapeutic target for AD.
Main Methods:
- Quantification of Rack1 levels in microglia from AD patients and AD model mice.
- Conditional knockout of Rack1 in microglia of AD model mice.
- Assessment of Aβ aggregation, neuroinflammation, cognitive function, astrocyte numbers and phagocytic activity.
- In vitro and in vivo experiments involving IGF1 and IGF1R inhibition.
Main Results:
- Rack1 levels were elevated in microglia of AD patients and mice.
- Microglial Rack1 knockout reduced Aβ aggregation, neuroinflammation, and cognitive deficits.
- Rack1 deficiency in microglia increased astrocyte numbers and phagocytic activity via IGF1 upregulation.
- IGF1R inhibition blocked these Rack1-deficiency-induced effects on astrocytes.
Conclusions:
- Microglial Rack1 is a significant contributor to Alzheimer's disease pathology.
- Microglial Rack1 influences astrocyte behavior and phagocytosis through the IGF1-IGF1R pathway.
- Targeting microglial Rack1 presents a promising therapeutic avenue for Alzheimer's disease treatment.
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