An Inflammatory Feedback Loop in the Aging Brain Contributes to Neurodegeneration

Scientists here report on a mechanism that might explain some fraction of the rising levels of chronic inflammation observed in the aging brain - though as in most such research, it is a proximate cause, and it isn't very clear as to how it relates to the known root causes of aging. Whatever that relationship might be, it is clear enough that with advancing age the immune system falls into a state of continual, inappropriate activation and inflammation. This disrupts many important processes in the normal maintenance of tissue function, and particularly so in the brain, where immune cells undertake a greater range of important activities than is the case elsewhere in the body.

The activity of microglial cells plays an important role in brain aging. These cells are part of the brain's immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation. This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled.

Endocannabinoids play an important role in this control. These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells. Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. However, microglial cells have virtually no CB1 and very low level of CB2 receptors. Researchers have now found that the brake signals do not communicate directly with the glial cells, but via middlemen - a certain group of neurons, because this group has a large number of CB1 receptors.

This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulator the other major glial cell type, the astroglial cells. During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle. Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.

It may be possible to break this vicious circle with drugs in the future. Tetrahydrocannabinol (THC) is a powerful CB1 receptor activator, even in low doses. Last year, researchers were able to demonstrate that THC can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.