# Noradrenergic signaling controls Alzheimer’s disease pathology via activation of microglial β2 adrenergic receptors

## TL;DR

This study shows that norepinephrine signaling through microglial β2 adrenergic receptors can influence Alzheimer’s disease pathology, suggesting a potential new therapeutic target.

## Contribution

The study identifies microglial β2 adrenergic receptors as a novel therapeutic target for modifying Alzheimer’s disease pathology.

## Key findings

- Loss of cortical norepinephrine projections precedes NE neuron degeneration in AD models.
- Microglia near plaques in 5xFAD mice downregulate β2AR expression early in amyloid pathology.
- Stimulating microglial β2AR signaling reduces amyloid pathology in AD models.

## Abstract

Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer’s disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain’s resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR gene expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.