Variants of the APOE gene (the most common labeled as APOE-ε2, APOE-ε3, and APOE-ε4) have been show to alter the risk of developing Alzheimer's disease. Work in recent years has pointed to effects on the behavior of microglia in the aging brain as the important mechanism is driving risk. Bad variants of APOE, predominantly APOE-ε4 in the population at large, lead to greater inflammation driven by activated and dysfunctional microglia. Good variants suppress that inflammation. Various lines of evidence suggest that lipid metabolism in microglia becomes disrupted with age, driving inflammatory behavior. APOE plays a number of important roles in lipid metabolism, and there are significant differences in the capabilities of the different APOE variants.
While some consensus exists in the research community regarding the high level view of the biochemistry noted above, there is much left to accomplish when it comes to fleshing out the fine details. Today's open access paper is an example of this research, aimed at better mapping the connection between APOE3 and inflammatory signaling. The researchers show that a rare APOE variant suppresses the cGAS-STING innate immune pathway that reacts to forms of molecular damage in the cell with inflammatory signaling. This reaction is useful in youth, but becomes maladaptive in cells in aged tissues, burdened with damage that provokes constant and excessive inflammation. That inflammation in turn drives the onset and progression of neurodegenerative conditions such as Alzheimer's disease.
Alzheimer's Protective Mutation Works by Taming Inflammation in the Brain
Alzheimer's disease has long defied scientific efforts to understand its causes and develop effective treatments. Growing evidence suggests that tau - not amyloid - is the key driver of neurodegeneration and cognitive decline. What determines an individual's susceptibility or resistance to tau toxicity remains poorly understood. The mutation APOE3-R136S - known as the "Christchurch mutation" as it was discovered in Christchurch, New Zealand - protects against tau pathology and cognitive deterioration despite extensive amyloid buildup, offers an important clue.
This rare mutation is found in the APOE gene encoding a cholesterol transport protein (apolipoprotein E). In 2019, scientists studying a Colombian family with hereditary early-onset Alzheimer's, which typically strikes by age 50, reported that one family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s. Despite high brain amyloid, she exhibited low levels of tau. Subsequent research, mostly in mouse models, has confirmed the Christchurch mutation's beneficial effects - but researchers still aren't sure how it exerts protection.In the new study, researchers engineered the Christchurch mutation into the APOE gene in mice that develop tau accumulation, and found that it protected the animals from hallmark Alzheimer's features -including tau accumulation, synaptic damage, and disruptions in brain activity. These protective effects were traced to suppression of the cGAS-STING pathway, an innate immune signaling cascade normally activated in response to viral threat but is chronically activated in Alzheimer's disease.
Researchers further discovered that the protective mechanism of the Christchurch mutation can be largely attributed to taming microglia, brain-resident immune cells. These cells and their inflammatory state in Alzheimer's have long been seen as potential drivers of the disease process. When the researchers treated mice with tau pathology using a small-molecule inhibitor of cGAS-STING signaling, they observed synapse-protecting effects and molecular changes in brain cells that closely resembled those seen with the protective mutation.
The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear.
Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the R136S mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation.
Treating E3 tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the R136S mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon pathway plays a central role in mediating the protective effects of R136S against tauopathy.
View the full article at FightAging
