Calming the brain's immune cells may curb damaging inflammation in Alzheimer's

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 University of Rochester Del Monte Institute for Neuroscience, 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.

New targets for future treatment

Traditionally, Alzheimer's has been seen as a problem of damaged brain cells due to plaque buildup. This study shows that a loss of norepinephrine's calming effect on microglia might be a key factor that makes the disease worse, even before large amounts of nerve cell damage occur. The findings also suggest that problems with the β2AR receptor could start very early in the disease process, meaning that future treatments might be more effective if started sooner rather than later.

Since activating the β2AR receptor in microglia reduced plaque buildup and inflammation, future drugs might be designed to target this specific receptor. By helping microglia maintain an anti-inflammatory response, these treatments could slow down or change the course of the disease. The research also hints that such treatments might need to be customized for each patient. This is because the effects can vary based on factors like biological sex and the disease's stage.

Additional co-authors include Alexis Feidler, Lia Calcines Rodriguez, MacKenna Cealie, Elizabeth Plunk, Herman Li, Kallam Kara-Pabani, Cassandra Lamantia, and Kerry O'Banion with the Del Monte Institute for Neuroscience. The research was supported with funding from the National Institute of Neurological Disorders and Stroke, the Alzheimer's Association, the National Institute of General Medical Sciences, and the University of Rochester.