Deactivating microglia reduces tau-linked brain damage in mice, study reveals

Written by Sharon Salt, Editor

In a recently published study in the Journal of Experimental Medicine, researchers have revealed that microglia – which are activated as tau tangles accumulate in the brain – may form the crucial link between protein clumping and brain damage. Their findings suggest that eliminating microglia significantly reduces tau-linked brain damage in mice and implies that suppressing these cells could prevent or delay the onset of dementia.

“Right now many people are trying to develop new therapies for Alzheimer’s disease, because the ones we have are simply not effective,” commented senior author, David Holtzman (Washington University School of Medicine, MO, USA). “If we could find a drug that specifically deactivates the microglia just at the beginning of the neurodegeneration phase of the disease, it would absolutely be worth evaluating in people.”

In previous studies, Holtzman and colleagues have demonstrated that microglia limit the development of a harmful form of tau. However, the team also suspected that microglia may be acting as a double-edged sword. Once the tau tangles have formed later in the disease course, the cells’ attempts to attack the tangles may harm neighboring neurons and contribute to neurodegeneration.

In order to understand the relationship between microglia and tau-driven neurodegeneration, the investigators genetically modified mice that carried a mutant version of human tau clumps together easily. According to the researchers, such mice start to develop tau tangles at approximately 6 months of age and by 9 months, the mice display signs of neurological damage.

Following this, the researchers genetically modified the mice to carry either the human variant of APOE4 or no APOE.

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When the mice were 6 months of age, the researchers fed one group with a compound to deplete microglia in their brains for 3 months, whilst others were given a placebo.

In mice that contained tau tangles and APOE4, the researchers noted that their brains had severely shrunken and were damaged by 9.5 months of age – this finding was observed when microglia were present. However, if the microglia were eliminated by using the compound tested, the brains of the mice were reported to be normal and healthy, with less evidence of harmful forms of tau despite the presence of APOE4.

In addition to this, mice with microglia and the mutant version of human tau but no APOE also exhibited minimal brain damage and fewer signs of tau-linked tangles. Further experiments also demonstrated that microglia require APOE to become activated. The researchers stated that microglia that had not been activated do not destroy brain tissue or promote the development of harmful forms of tau.

“Microglia drive neurodegeneration, probably through inflammation-induced neuronal death,” explained first author, Yang Shi (Washington University School of Medicine). “But even if that’s the case, if you don’t have microglia, or you have microglia but they can’t be activated, harmful forms of tau do not progress to an advanced stage, and you don’t get neurological damage.”

The findings of this study implicate that microglia are the linchpin of the neurodegenerative process and are an appealing target to prevent cognitive decline. According to the study authors, the compound tested in the study to deplete microglia includes side effects that make it a poor candidate for drug development. However, it may point researchers in the right direction to other compounds that are more tailored to microglia.