Microglia discovery offers clues to Alzheimer’s progression

A new study from the University of Virginia School of Medicine has demonstrated that the brain’s immune cells, known as microglia, play a crucial and previously overlooked role in regulating blood flow in the brain. The discovery could lead to new therapeutic strategies for Alzheimer’s and other neurodegenerative conditions.

Led by Dr Ukpong B. Eyo from UVA’s Department of Neuroscience, the research team found that microglia play a vital role in regulating how effectively capillaries deliver oxygen and nutrients to brain tissue. They suggest disruptions in this process could drive or worsen conditions such as Alzheimer’s, vascular dementia and Parkinson’s disease.

“For some time now, microglia have been suggested to play important roles in regulating vessel function. With this study, we have provided the most definitive evidence that they do regulate blood flow to the brain, specified the location of this function to the brain’s small vessels or capillaries and identified an enzyme that they use to do this,” said Eyo, a member of UVA’s Center for Brain Immunology.

High-energy demands, delicate balance

Although the brain accounts for only 2 percent of body weight, it consumes approximately 20 percent of the body’s total energy. This demand is met by a 400-mile-long network of blood vessels – with the smallest capillaries playing a vital role in nutrient and oxygen delivery.

Previous studies have linked dysfunction in myeloid cells – a group of immune cells that includes microglia – with impaired brain oxygenation and elevated carbon dioxide levels . However, Eyo’s team set out to pinpoint the specific cells involved and to determine the consequences when their function is disrupted.

They discovered that microglia are crucial for maintaining the “tone” of capillaries – essentially how dilated or constricted they are. When microglia were removed, capillary diameter shrank and blood flow decreased. Restoring the microglia reversed these effects.

Targeting microglia for therapeutic benefit

The study also identified a specific enzyme used by microglia to regulate capillary tone. This enzyme has previously been explored as a target in Alzheimer’s treatment, though with inconsistent results.

“The microglial enzyme identified in this study has been targeted heretofore in patients with Alzheimer’s disease, albeit with mixed results,” said first author Dr William A. Mills III. “Our study suggests that these therapeutics would have maximal benefit if prescribed according to the therapeutic window of microglia in Alzheimer’s – a focus in our ongoing research.”

“We have determined that all microglia are capable of regulating basal capillary tone as opposed to a subset of them, thus revealing their importance to meeting energy demands in the brain,” Mills added.

A new frontier in brain health research

Understanding how microglia interact with other cells to maintain healthy blood flow is now a top research priority. The UVA team hopes that exploring this communication network could lead to breakthroughs in treating or even reversing neurodegenerative diseases.

“Now that we have identified a novel role for microglia in blood vessel structure and function as well as a specific enzyme involved, we are poised to examine how this enzyme and microglial functions change, and to subsequently develop therapies to reduce these changes during neurodegenerative diseases broadly and in Alzheimer’s disease especially,” said Eyo.

“However, questions abound that our group will pursue – eg, do the microglia regulate the small capillaries independently or in concert with other brain cells? When during development do microglia begin to play this role, and is this role also important in neurodevelopmental disorders where vascular function is also compromised? Can microglial replacement facilitate blood flow rejuvenation in neurodegenerative diseases? These are exciting questions we hope to answer in the near future.”

By revealing the hidden roles of microglia in brain vasculature, the team is laying crucial groundwork for future therapies that could protect – and potentially restore – cognitive function in a range of brain disorders.