Switching Brain's Defenses to Protect Against Alzheimer's

New research suggests that certain immune cells in the brain may be vital in protecting against Alzheimer's disease, opening possibilities for treatments aimed at encouraging these cells into a defensive state.

Previous studies indicated that microglia, a type of immune cell in the brain, can both combat and exacerbate Alzheimer's symptoms due to their inflammatory responses. In this study, an international team explored how microglia switch between these helpful and harmful roles.

Using mouse models, neuroscientist Pinar Ayata from the Icahn School of Medicine and colleagues discovered that when microglia encounter amyloid-beta protein clumpshallmarks of Alzheimer'sthey enter a specialized neuroprotective state.

"Microglia are not merely destructive agents in Alzheimer'sthey can act as protectors of the brain," says Anne Schaefer, neuroscientist at Icahn School of Medicine in New York. "This expands our understanding of the adaptability of microglia and their diverse roles in brain function."

Researchers identified two key traits of this microglia subtype: reduced levels of PU.1, a protein linked to Alzheimer's, and increased expression of CD28, a protein critical to immune function. Microglia exhibiting this profile were more effective at slowing amyloid-beta accumulation and limiting tau protein clumps, another toxic factor in Alzheimer's.

When CD28 production was blocked in mice, harmful, inflammation-causing microglia became more prevalent, and amyloid-beta plaques increased.

These findings align with previous research showing that individuals genetically predisposed to lower PU.1 expression tend to develop Alzheimer's later in life. "This offers a mechanistic explanation for why reduced PU.1 is associated with lower Alzheimer's risk," says geneticist Alison Goate from Icahn School of Medicine.

While this natural protective mechanism exists, it is insufficient to fully prevent disease progression. Researchers hope that therapies could one day boost this microglia subtype, though confirmation in humans is required.

Alzheimer's is highly complex, involving multiple risk factors, suggesting that effective treatment may need to target several mechanisms simultaneously. One approach may be to convert microglia into their neuroprotective state.

The study also highlights broader connections between Alzheimer's and the immune system. Modified microglia in mice act similarly to T cells found elsewhere in the nervous system. "This discovery coincides with growing recognition of regulatory T cells as key immune regulators, emphasizing a shared principle of immune control," explains epigeneticist Alexander Tarakhovsky of Rockefeller University. "It also opens doors for immunotherapy approaches to Alzheimer's."

The research has been published in Nature.

Author: Sophia Brooks