Microglia are innate immune cells resident in the brain. They are quite similar to the macrophages found elsewhere in the body, but specialized to the central nervous system. In addition to the tasks of chasing down pathogens and participating in regenerative from injury, they are also involved in the processes of maintaining and altering synaptic connections between neurons. Like macrophages, microglia can adopt different packages of behavior in response to environment and circumstances. This is commonly described in terms of the broad M1 and M2 states, where M1 is pro-inflammatory and aggressive where M2 is anti-inflammatory and regenerative. With advancing age, ever more microglia become inflammatory, and this is thought to be an important contribution to neurodegenerative conditions.
Why do microglia become inflammatory in aged tissues? There are any number of contributing mechanisms. There is the inflammatory signaling generated by the rest of the aged immune system, biasing microglia to joining in. Senescent cells also generate inflammatory signaling. Aging diminishes drainage of cerebrospinal fluid from the brain, allowing metabolic waste products to build up and aggravate cells. These waste products include the misfolded and altered proteins such as amyloid-β that are characteristic of neurodegenerative conditions. And so forth; many of the forms of molecular damage and cell dysfunction that occur with age tend produce a maladaptive inflammatory reaction from microglia. Some of this is quite direct, but today’s open access paper describes a more indirect consequence of the underlying causes of aging that acts to increase microglial inflammation.
Modulating the brain’s immune system may curb damage in Alzheimer’s
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. 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 β2AR 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. 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.
Noradrenergic signaling controls Alzheimer’s disease pathology via activation of microglial β2 adrenergic receptors
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 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.
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