Modulating the Brain’s Immune System May Curb Damage in Alzheimer’s

Thursday, April 17, 2025

New research suggests that calming the brain’s immune cells might prevent or lessen the damaging inflammation seen in Alzheimer’s disease. The study points to the key role of the hormone and neurotransmitter norepinephrine, and this new understanding could pave the way for more focused treatments that start earlier and are tailored to the needs of each person.

“Norepinephrine is a major signaling factor in the brain and affects almost every cell type. In the context of neurodegenerative diseases such as Alzheimer’s disease, it has been shown to be anti-inflammatory,” said Ania Majewska, PhD, with the Del Monte Institute for Neuroscience at the University of Rochester, and senior author of the study, which appears in the journal Brain, Behavior, and Immunity. “In this study, we describe how enhancing norepinephrine’s action on microglia can mitigate early inflammatory changes and neuronal injury in Alzheimer’s models.”

Brain Chemicals & Immune Cells

The research, which was conducted in mice, included teams from two labs, combining research programs studying the complex role of the brain’s immune system and the role of inflammation in Alzheimer's. Led by Linh Le, PhD, a graduate student in both labs, the researchers focused on norepinephrine, a chemical in the brain that helps control inflammation. In our brains, immune cells called microglia usually help keep things in balance. Microglia have a receptor called β2AR, which acts like a “switch” and directs the cells to respond to norepinephrine and calm down inflammation.

In Alzheimer’s disease and as we age, this calming switch becomes less active, especially in areas of the brain where harmful protein clumps called amyloid plaques build up. As these plaques form, the nearby microglia lose more of their β2AR receptors, making it harder for them to fight inflammation.

When scientists removed or blocked the receptor, the brain’s damage worsened: more plaques, increased inflammation, and more harm to brain cells. On the other hand, when they stimulated or "turned up" the receptor, the harmful effects were reduced. Interestingly, the results appeared to depend on factors like the animal’s sex and how early the treatment started.

Brain Immune Cells May also be From Mars and Venus

Tuesday, January 21, 2025

Researchers find that microglia function differently in males versus females

A collision happens. Someone is hurt, a head injury, a concussion. Just as the first responders arrive to help the person, inside the brain, another “crew” of responders is busy clearing debris and repairing injured tissue.

This crew is called the microglia—the immune cells of the central nervous system. Microglia are imperative to maintaining neuronal function by clearing toxins in the brain and central nervous system. But if they are overactive, they can damage neurons instead and, in some cases, have been found to promote the progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s.

During development, there are known sex-related differences in how microglia function. But into adulthood, there was thought to be less variation in how they behave. New research from the Del Monte Institute for Neuroscience at the University of Rochester finds that microglia function may not be as similar across sex as once thought. This discovery could have broad implications for how diseases like Alzheimer's and Parkinson's are approached and studied, and points to the necessity of having gender-specific research. It is already known that more women are diagnosed with Alzheimer’s and more men are diagnosed with Parkinson’s, but it’s unclear why.

“It is a fortuitous finding that has repercussions for what people are doing in the field, but also helps us understand microglia biology in a way that people may not have been expecting,” said Ania Majewska, PhD, professor of Neuroscience and the senior author of a study out today in Cell Reports that shows how microglia respond differently in adult male versus female mice when given an enzyme inhibitor to block its microglia survival receptor. “This research has a lot of ramifications for microglia biology and as a result all these diseases where microglia are important in a sex-specific manner.”

Pexidartinib or PLX3397 is an enzyme inhibitor commonly used to remove microglia in the lab setting to help researchers better understand the role of these cells in brain health, function, and disease. PLX3397 is also used to treat the rare disease tenosynovial giant cells tumors (TGCT), a condition that causes benign tumors to grow rapidly in the joints.

Researchers in the Majewska Lab were using PLX3397 in male versus female experiments but continued to run into difficulties, so they decided to take a different approach with the inhibitor. Instead of using it to ask other questions, they decided to better understand how microglia were responding to the drug in males versus females.