Several Alzheimer's Associated Gene Variants Appear to Affect the Efficiency of Microglia

Microglia are innate immune cells of the brain, similar to macrophages in the rest of the body, but with a larger portfolio of activities. They are not just chasing down pathogens and cleaning up molecular waste, but are also deeply involved in maintaining the function and connectivity of neurons in brain tissue. Here, researchers note that several genetic variants that are either problematic or protective when it comes to Alzheimer's disease risk and progression affect the ability of microglia to clear amyloid-β aggregates from brain tissue. While therapies targeting amyloid-β accumulation have so far failed to produce meaningful clinical benefits in patients, perhaps because other processes have taken over as the dominant cause of pathology in later stage Alzheimer's disease, increased aggregation of amyloid-β is clearly associated with the condition, and is equally clearly the cause of toxic biochemistry that can harm cells.

Alzheimer's disease is the most common form of dementia with more than 40 million affected people worldwide. To this day, there are no existing therapies for the effective prevention or treatment of the disease. Many recently identified Alzheimer's disease-associated risk genes are expressed preferentially or exclusively in microglia, the immune cells of the brain. A recent study investigated the role of the microglia-specific Plcg2-P522R genetic variant in Alzheimer's disease and found that it enhances several immune cell-specific functions.

A genome-wide association study from 2017, which included a Finnish cohort of Alzheimer's disease patients and healthy controls, identified Alzheimer's disease-associated risk loci in three genes, TREM2, ABI3, and PLCG2, which are mainly expressed in microglia. Several genetic variants of the TREM2 gene have been found to increase the risk for Alzheimer's disease. These TREM2 variants lead to a partial loss of function of the receptor and impair the activation of microglia. Consequently, the removal of β-amyloid, which accumulates in the brain during Alzheimer´s disease, is reduced. Recently, it has been shown that the phospholipase C gamma 2 (PLCγ2) enzyme is involved in the signaling pathway initiated by TREM2. The PLCG2-P522R variant reduces the risk of developing Alzheimer's disease, but its effects on immune cell functions have not been previously described.

"It is interesting how several Alzheimer's disease-associated risk genes affect microglial cell functions through the same signaling pathway. It shows that targeting this pathway and the cellular functions it regulates may have significant therapeutic potential in the future."



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