Do microglia hold the key to stop Alzheimer’s disease?

Summary: Mouse models and human brain tissue studies reveal microglia react to amyloid beta earlier in older females. Findings may provide avenues for the development of new drugs to help treat the neurodegenerative disease.

Source: VIB

A Leuven research team led by Prof. Bart De Strooper (VIB-KU Leuven, UK DRI) 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 defence in the brain.

“The response of these important support cells to the accumulation of toxic amyloid beta may have a big effect on the disease process,” says Alzheimer expert Bart De Strooper (VIB-KU Leuven, UK DRI). “That’s why we wanted to understand better the microglial response to amyloid beta and how it may differ across individuals.”

The activation state of 10,000 cells

“We know microglia get involved in Alzheimer’s disease by switching into an activated mode,” explains Dr. Carlo Sala Frigerio. “We were interested to know if aging in the presence or absence of amyloid beta deposition would affect this activation.” Sala Frigerio worked in De Strooper’s lab in Leuven and recently started his own group at the UK Dementia Research Institute in London.

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.”

This shows microglia in brain samples
t-SNE plots as in (B), colored by the level of ln normalized expression of selected genes. Clusters of TRMs and ARMs display increased expression of Apoe and inflammation markers (Cst7) and concurrently display a reduction of homeostatic markers (P2ry12). Two distinct regions of the ARMs cluster display increased expression of MHC class II genes (H2-Aa, H2-Ab1, and Cd74), suggesting the existence of microglial subpopulations. Further, a small subset of the ARMs cluster displays an enrichment for tissue repair genes (Spp1, Gpnmb, and Dkk2). The ARMs cluster also displays differential expression of several AD-related genes (e.g., Ctsb, Bin1, and Pld3) compared to clusters of H1Ms and H2Ms. The cluster of IRMs is enriched for interferon genes (Ifit3, Oasl2, and Irf7). The image is credited to Frigerio et al.

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.

Targeting microglia activation

“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 De Strooper. “In other words, different Alzheimer’s risk factors converge on the activation response of microglia.”

Both De Strooper and Sala Frigerio 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.”

About this neuroscience research article

Media Contacts:
Nicholas Weiler – VIB
Image Source:
The image is credited to Frigerio et al.

Original Research: Open access
“The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques”. Sala Frigerio et al. Cell Reports. doi:10.1016/j.celrep.2019.03.099


The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques

• Exposure to Aβ in AD potentiates a microglia response present during normal aging
• This microglia response is heterogeneous with potential synaptotoxic subtypes
• Microglia in female mice develop this response faster than in male mice
• Apoe deletion blocks the main response of microglia to Aβ

Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female AppNL-G-F mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. 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. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. 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.

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