The brain immune cells known as microglia are known to have a complicated relationship with Alzheimer’s disease—and it just got more complicated. When microglia respond to the accumulation of amyloid-β plaque, a hallmark of Alzheimer’s, they attack, potentially slowing disease progression, but they may also harm neurons. And what about the formation of amyloid-β plaque in the first place? Do microglia play a role here, too? Yes, according to scientists based at the University of California, Irvine. Microglia, the scientists reported, contribute to plaque formation in the early stages of Alzheimer’s disease.

To arrive at this finding, the scientists, led by associated professor of neurobiology and behavior Kim Green, PhD, took microglia out of the equation and then observed what happened. Working with a mouse model of Alzheimer’s, the scientists administered a drug that inhibits a cell signaling mechanism essential to microglia survival. Where microglia were eliminated from the brains of mice, amyloid-β plaque formation was prevented.

Green and colleagues say that their discovery holds promise for creating drugs that could prevent Alzheimer’s disease. “We are not proposing to remove all microglia from the brain,” Green clarified, noting the importance of microglia in regulating other brain functions. “What could be possible is devising therapeutics that affect microglia in targeted ways.”

Detailed results from the Green group’s microglia experiments appeared August 21 in the journal Nature Communications, in an article titled, “Sustained microglial depletion with micrCSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model.” CSF1R refers to colony-stimulating factor 1 receptor, which necessary for microglia viability. CSF1R inhibition is, in fact, the only currently available method capable of achieving sustained long-term microglial elimination.

“We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development,” the article’s authors wrote. “We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia.”

Green and colleagues were aware that previous research had shown most Alzheimer’s risk genes are turned on in microglia, suggesting these cells play a role in the disease. “However, we hadn’t understood exactly what the microglia are doing and whether they are significant in the initial Alzheimer’s process,” he pointed out. “We decided to examine this issue by looking at what would happen in their absence.”

Besides showing that microglia are a necessary component in the development of Alzheimer’s, the Green group confirmed that when plaques are present, microglia perceive them as harmful and attack them. However, the attack also switches off genes in neurons needed for normal brain functioning. “This finding,” Green emphasized, “underlines the crucial role of these brain immune cells in the development and progression of Alzheimer’s.” Green and colleagues also performed transcriptional analyses of the residual plaque-forming microglia. The results? A disease-associated microglia profile.

In microglia-depleted areas of the brain, the scientists observed, amyloid-β deposits in cortical blood vessels are reminiscent of cerebral amyloid angiopathy. Also, in hippocampal neurons, the upregulation of genes associated with Alzheimer’s progression is reversed.

“[We] have designed and created a specific CSF1R inhibitor, PLX5622, that allows for the sustained and specific elimination of microglia,” the authors of the Nature Communications article concluded. “These results indicate that microglia appear to contribute to multiple facets of AD etiology—microglia appear crucial to the initial appearance and structure of plaques, and following plaque formation, promote a chronic inflammatory state modulating neuronal gene expression changes in response to Aβ/AD pathology.”

Green added that microglial depletion offers an avenue for better understanding other brain disorders. “These immune cells are involved in every neurological disease and even in brain injury,” he said. “Removing microglia could enable researchers working in those areas to determine the cells’ role and whether targeting microglia could be a potential treatment.”

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