SIRT2 Inhibition in Reactive Astrocytes Reduces their Harmful Impact in Alzheimer’s Disease

Reactive astrocytes in brain tissue are those that have become inflammatory in response to the local environment. With aging this becomes a prevalent phenomenon, driven by forms of molecular damage characteristic of aging, which range from greater inflammatory signaling from other cells, including senescent cells, to the build up of metabolic waste in the brain as drainage of cerebrospinal fluid falters. Widespread astrocyte reactivity is maladaptive, and contributes to the onset and progression of neurodegenerative conditions. The research community tends not to focus on how to prevent reactivity, such as by repairing the damage of aging, but rather on the worse course of trying to force reactive astrocytes into better behavior, one aspect at a time. The research here is one example of this strategy in practice. Even if successful, the reactive astrocytes remain present, causing other problems in other ways.

Astrocytes, once thought to only support neurons, are now known to actively influence brain function. In Alzheimer’s disease, astrocytes become reactive, meaning they change their behavior in response to the presence of amyloid-beta (Aβ) plaques, a hallmark of the disease. While astrocytes attempt to clear these plaques, this process triggers a harmful chain reaction. First, they uptake them via autophagy and degrade them by the urea cycle, as discovered in previous research. However, this breakdown results in the overproduction of GABA, which dampens brain activity and leads to memory impairment. Additionally, this pathway generates hydrogen peroxide (H2O2), a toxic byproduct that causes further neuronal death and neurodegeneration.

Researchers set out to uncover which enzymes were responsible for excessive GABA production, hoping to find a way to selectively block its harmful effects without interfering with other brain functions. Using molecular analysis, microscopic imaging, and electrophysiology, the researchers identified SIRT2 and ALDH1A1 as critical enzymes involved in GABA overproduction in Alzheimer’s-affected astrocytes. SIRT2 protein was found to be increased in the astrocytes of the commonly used AD mouse model as well as in post-mortem human AD patient brains.

“When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production. While we expected reduced GABA release, we found that only short-term working memory of the mice was recovered, and spatial memory was not. This was exciting but also left us with more questions. We found that inhibition of SIRT2 continued H2O2 production, indicating that neuronal degeneration might continue even though GABA production is reduced.”