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Whether to fight Alzheimer's disease or become an accomplice is a matter of a gene

Time:2023-09-18 09:06:32     Views:270

International Business Department           Liu Bojia           September 18, 2023

  Each year, about 10 million people worldwide are newly diagnosed with Alzheimer's disease. With the exception of a small number of patients due to family inheritance, the vast majority - about 95% - have episodic Alzheimer's disease. This also means that there may be far more genetic variants affecting Alzheimer's disease risk than was thought in the past.


  Recently, a new study published in Immunity, a subseries of Cell, identified a new genetic variant that affects the function of the brain's immune system by regulating microglia, promising a new target for treating Alzheimer's disease.


  Microglia are immune cells resident in the brain. In recent years, genome-wide association studies have revealed that such cells play a key role in the immune response during the course of Alzheimer's disease. In this study, the scientists analyzed in detail how PLCG2, a phospholipase gene highly expressed by microglia, precisely influences the development of Alzheimer's disease.


  In previous studies, it had been found that mutations in just one site of this gene (e.g., P522R) could play a protective role against Alzheimer's disease. The new study further found that the gene may also be a "driver" of Alzheimer's disease, increasing the risk of the disease, because of a mutation in just one base (e.g., M28L).


  In the experiments, the researchers constructed two transgenic mice, one expressing the protective PLCG2-P522R variant and one expressing the PLCG2-M28L variant, which increases the risk of the disease. These mice themselves expressed amyloid proteins associated with Alzheimer's disease, on the basis of which more amyloid plaques were produced in the brains of the PLCG2-M28L transgenic mice and fewer plaques in the brains of the PLCG2-P522R transgenic mice, as compared to wild-type (WT).


  Meanwhile, analyzing microglia from different mice revealed that the protective PLCG2 transgenic mice brains had a high concentration of microglia around amyloid plaques and further promoted the immune response associated with microglia. However, in the brains of risky PLCG2 transgenic mice, microglia were less likely to aggregate around plaques, and these microglia that had lost their normal function had a poorer immune response and function. 


  Interestingly, even though PLCG2-P522R transgenic mice had amyloid plaques in their brains, mice with this gene mutation did not have further deterioration in cognitive function compared to normal mice, and long-term potentiation of neurons, which is closely related to learning memory function (LTP), was not significantly affected.


  Finally, through single-cell RNA sequencing technology, the team identified different clusters of microglia, including homeostatic, transitional, IFN-responsive, and activated states. The results showed that in the brains of risky PLCG2 transgenic mice, microglia were more in the transition state; while in the brains of protective PLCG2 transgenic mice, microglia were mainly in the activated state, and the number of steady-state microglia was significantly reduced. 


  Taken together, this study provides insight into the effects of different genetic variants of PLCG2 on microglia function as well as the development of amyloid plaque pathology, providing important insights for future Alzheimer's disease treatment. The study authors note that future research directions will likely focus on further understanding the mechanisms that regulate PLCG2's function, with the aim of being able to slow or even halt cognitive decline in AD patients.


  The study's corresponding author is Professor Gary Landreth of Indiana University School of Medicine, and the article's first author is Dr. Andy Tsai, who is currently conducting research at Stanford University School of Medicine.

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