Summary: The” Christchurch mutation” or APOE3-R136S, a rare genetic mutation, appears to block the body’s immune cells from aggressive signaling. Researchers discovered that this mutant dampens the crucial innate immune system that is excessively activated in Alzheimer’s and other neurological disorders, the cGAS-STING pathway.
Despite having high amyloid levels, mice engineered with the gene showed lower tau accumulation, neuronal damage, and brain dysfunction, which are hallmarks of Alzheimer’s. The findings suggest that cGAS-STING could be used to imitate the protective effects of the mutation and provide a novel approach to Alzheimer’s treatment.
Important Information
- Safe Pathway Identified: The Christchurch gene blocks cGAS-STING, a crucial immune system in Alzheimer’s.
- Pharmaceutical Potential: The inhibitory effects of the mutation on brain function were mirrored in mice by blocking this route.
- Focus Shift: Findings support the hypothesis that Alzheimer’s growth is influenced by disease and tau rather than just amyloid.
Weill Cornell University as the resource
According to a preliminary study led by researchers at Weill Cornell Medicine, a unique gene mutation that difficulties Alzheimer’s disease does so by dampening inflammation signaling in brain-resident immune tissue.
The finding strengthens the growing evidence that mind inflammation is a important cause of degenerative diseases like Alzheimer’s and that it may serve as a crucial therapeutic target for these conditions.
The researchers examined the effects of the APOE3-R136S mutation, known as the” Christchurch mutation,” in the study, which was just discovered to delay hereditary early-onset Alzheimer’s.
The cGAS-STING road, an innate defense indicating sequence that is excessively activated in Alzheimer’s and other neurological conditions, is blocked by the Weill Cornell Medicine researchers.
The researchers discovered that important protective effects of the gene were replicated by medicinally blocking the cGAS-STING route with a drug-like receptor in a preliminary design.
According to study senior author Dr. Li Gan, the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases and director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine,” this study suggests that inhibiting this cGAS-STING pathway may make the brain more immune to the Alzheimer’s process, perhaps in the face of substantial tau accumulation.”
Drs. were the study’s co-first authors. During the study, Sarah Naguib, Chloe Lopez-Lee, and Eileen Ruth Torres, all postdoctoral researchers, were all employed by the Gan Laboratory.
At least seven million adults in the United States are affected by Alzheimer’s disease, which has long defied scientific efforts to understand its causes and develop effective treatments. Evidence from growing evidence suggests that tau, rather than amyloid, is the main cause of cognitive decline and neurodegeneration.
What factors into a person’s susceptibility or resistance to tau toxicity are still poorly understood. Important information can be found in the Christchurch mutation, which, despite extensive amyloid buildup, guards against tau pathology and cognitive decline.
This uncommon mutation was first discovered by a laboratory in Christchurch, New Zealand, in the APOE gene, which encodes a cholesterol transport protein ( apolipoprotein E). One family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s in 2019, according to researchers studying a Colombian family with hereditary early-onset Alzheimer’s, which typically strikes at age 50.
She had low levels of tau despite having high brain amyloid. The Christchurch mutation’s beneficial effects have been confirmed by subsequent research, primarily in mouse models, but researchers are still unsure how it exerts protection.
The Christchurch mutation in the APOE gene in mice that accumulate tau was engineered by Dr. Gan’s team to protect the animals from hallmark Alzheimer’s symptoms, including tau accumulation, synaptic damage, and brain disruptions.
activity. The cGAS-STING pathway, an innate immune signaling cascade that is typically activated in response to viral threat but is chronically activated in Alzheimer’s disease, was the cause of these protective effects.
” We are particularly encouraged that this mutation ameliorates disease at a level of brain function, which has not previously been demonstrated,” said Dr. Naguib.
Further research by Dr. Gan and colleagues demonstrated that brain-resident immune cells, or microglia, play a significant role in the protective mechanism behind the Christchurch mutation. These cells and their inflammatory state in Alzheimer’s have long been thought to be potential contributors to the disease process.
When the researchers used a small-molecule inhibitor of cGAS-STING signaling to treat mice with tau pathology, they observed synapse-protection effects and molecular changes in brain cells that resembled those seen with the protective mutation.
The team is now looking into cGAS-STING signaling’s role in other neurodegenerative disorders and testing inhibitors on various animal models of these disorders in light of growing evidence that cGAS-STING signaling contributes to disease progression.
Although Dr. Gan argued that” we can’t genetically modify the uncommon Christchurch mutation to prevent Alzheimer’s,” targeting the same pathway that it controls, cGAS-STING, might provide a novel treatment option for Alzheimer’s and other potentially neurodegenerative conditions.
About this research in genetics and Alzheimer’s disease
Author: Barbara Prempeh
Source: Weill Cornell University
Contact: Barbara Prempeh – Weill Cornell University
Image: The image is credited to Neuroscience News
Original Research: Disclosed access.
Li Gan et al. claim that the mutation in the APOE3  gene, R136S , confers resilience against tau pathology by inhibiting the cGAS-STING-IFN pathway. Immunity
Abstract
The mutation in the , APOE3  gene, R136S , and cGAS-STING-IFN pathway, inhibits the cGAS-STING-IFN pathway, which confers resilience against tau pathology.
Despite having a causal, PSEN1, mutation, and high amyloid burden in the carrier, the Christchurch mutation ( R136S ) in the , APOE3 , and ( E3S/S ) gene is linked to attenuated tau load and cognitive decline.
However, it is still unclear what molecular mechanisms are responsible for the tau-induced neurodegeneration caused by the E3S/S mutation.
On a tauopathy background, we replaced mouse , Apoe , with wild-type human , APOE3 , or , APOE3S/S .
The mutation prevented tau-induced synaptic loss, myelin loss, and a decrease in hippocampal theta and gamma power by reducing the andrp, R136S , and tau load.
In addition, the mutation suppressed cGAS-STING pathway activation in both mouse and human microglia and reduced interferon responses to tau pathology.
Using a cGAS inhibitor to treat mice with tauopathy, and protect them from tau-induced synaptic loss and induced transcriptomic changes similar to the , R136S , mutation across brain cell types.
Thus, the microglial cGAS-STING-interferon ( IFN) pathway is largely involved in the mediating of tauopathy’s protective effects.
