Microglial response to amyloid plaque depends on age, sex and genes

Microglial response to amyloid plaque depends on age, sex and genes

A research team studied how specialized brain cells called microglia respond to the accumulation of toxic proteins in the brain, a feature typical of Alzheimer's. The three major disease risk factors for Alzheimer's--age, sex and genetics--all affect microglia response, raising the possibility that drugs that modulate this response could be useful for treatment.

One of the hallmarks of Alzheimer's disease is the presence of so-called amyloid plaques in the brain. Research suggests that these plaques trigger a series of processes in which microglia play a central role. Microglia are specialized brain cells that act as the first and main form of immune defense in the brain.

The researchers used a genetic mouse model in which amyloid beta progressively accumulates, mimicking the disease process in human patients. The team analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from different brain regions of both male and female mice at different disease stages.

"We found that the microglial responses to amyloid beta were complex but could essentially be catalogued into two major activation states. The same two activation states that are found during normal ageing, but then activation was slower and less pronounced."

Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1
) and are strongly enriched with Alzheimer’s disease (AD) risk genes. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

In female mice, the microglia reacted earlier to amyloid beta, especially if the mice were older. Similar findings resulted from analyzing the microglia in a different Alzheimer mouse model and in human brain tissue.

"Our data indicate that major Alzheimer risk factors, such as age, sex and genetic risk, affect the complex microglia response to amyloid plaques in the brain," says the author. "In other words, different Alzheimer's risk factors converge on the activation response of microglia."

The authors believe that the response of individual microglia will largely depend on their direct environment within the brain. "A particular challenge will be to dissect the distribution of microglia in different activation states across the brain. Such a detailed dissection could lead to a whole set of new drug targets that could be useful to tune the microglia response in a beneficial way."