Microglial Proliferation in Alzheimer's Model Mice
Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. In addition to mounting a defense against pathogens and cleaning up metabolic waste, these cells are involved in maintenance of neural connections. Ever more attention is given of late to chronic inflammation in the aging of the brain, and microglia are known to become more active and inflammatory with advancing age, amplifying inflammatory signaling in ways that are disruptive to tissue function.
Some of this microglial inflammatory signaling is due to a growing fraction of senescent microglia, one facet of the rising numbers of senescent cells of many different types throughout the body with age, but the rest is a mixed bag of reactions to damage and dysfunction in brain tissue. This includes issues internal to cells, such as mitochondrial dysfunction that leads to mislocated mitochondrial DNA fragments and an inflammatory reaction to that DNA, issues external to cells, such as the growing presence of misfolded amyloid-β associated with Alzheimer's disease, and structural problems such as leakage of the blood brain barrier that allows inappropriate cells and molecules to pass into the brain and provoke an immune response.
It is possible to clear the entire population of microglia from the brain using CSF1R inhibitors such as pexidartinib. New microglia repopulate the brain within a few weeks. Some researchers have considered this as a way to reset some of the excessive inflammatory activity. It produces benefits in mice, but too little work has been carried out to date to determine just how long such a respite might last in humans. Other researchers are interested in finding ways to adjust the state of microglia from pro-inflammatory M1 to anti-inflammatory M2, analogous to the established research into manipulation of macrophage state. This is also promising, and something that could be achieved with existing drugs. It is also not very far advanced towards the clinic, however.
Microglial-related neuroinflammation affects the trajectory of Alzheimer's disease (AD), and an individual's susceptibility to AD may depend in part on the behavioral phenotype of microglia. Understanding the immune response patterns of microglia and the behavioral interaction mode of microglia with other cell types allows for the accurate targeting of microglia with impaired or abnormal responses, which has great potential for developing effective tools to delay aging and avoid neurodegenerative diseases.
In the present study, scRNA-seq analysis was performed on hippocampal samples from wide type (WT) and 5× familiar Alzheimer's disease (5× FAD) mice at 2-, 12-, and 24-month of age to map the clustering of hippocampal cells during aging and AD. We focused on the immune behavior and phenotypic characteristics of microglia. The outside and inside signal flow in the population of microglia reveals the crosstalk between neuroinflammatory pathways and cell behavior interactions guided by immune responses in the hippocampus. Our study found that blood-brain barrier (BBB) injury may increase the percentage of microglia during the progression of aging and AD.
In rodents, microglia account for 5%-12% of all central nervous system (CNS) cells and are distributed throughout the parenchyma. We found that microglia made up over 12% of the total hippocampal cells, about 45%-55% in WT mice and 45%-78% in 5× FAD mice. Maintenance of the brain microglial population is independent of circulating monocytes generated in the bone marrow and depends primarily on the self-renewal of microglia. Our scRNA-seq results showed that in WT mice, the number of microglia increased significantly at 24 months, but the fraction of microglia in the total hippocampal cells remained stable.
In the hippocampus of 5× FAD mice, the number and proportion of microglia increased abnormally at 12 months, and at 24 months, the number of microglia tended to level off compared with the 12-month of age. The accumulation of amyloid-β also showed a similar trend. This may be one of the reasons for the induction of microglial activation and proliferation. In addition, from 2 to 24 months, the PTN growth signal received by microglia in WT mice tended to decrease, suggesting that excessive growth of microglia was continuously suppressed. In 5× FAD mice, the growth and development signals were significantly enhanced at 12 months compared to those at 2 months. The uncontrolled proliferation of microglia is clearly not spontaneous but arises from environmental stimuli.