Summary: Researchers have discovered that two biological variations, APOE4 and TREM2 R47H, along cause a damaging inflammatory response in mental immune cells, especially in women. This reaction leads to more serious mental injury, including beta protein clumps, which are linked to Alzheimer’s disease development.
The study found that adult mice with these variants experienced increased swelling in brain defensive cells, or microglia, which turn on and unlock the cGAS-STING pathway. These results suggest that preventing and treating Alzheimer’s by targeting defensive pathways in a sex-specific way may be a successful approach.
Important Facts:
- APOE4 and TREM2 varieties along cause harmful mental disease in women.
- Microglia function in women with these variations accelerates Alzheimer’s harm.
- Targeting defense pathways may offer novel, sex-specific Alzheimer’s remedies.
Origin: Weill Cornell University
In a preclinical model, researchers at Weill Cornell Medicine discovered that two genetic variants that jointly raise the risk of Alzheimer’s disease ( AD ) cause a harmful inflammatory response in the brain’s immune cells, particularly in females.
The , studies, published Sept. 30 in , Neuron, emphasize the importance of considering gender differences in Alzheimer’s study – a move that could eventually lead to more precise and effective solutions.
Worldwide, there are millions of people who are affected by Advertising, with women being overwhelmingly affected; nearly twice as many women develop the disease as men. To improve healing approaches, researchers are trying to determine the schedule for these variations in risk.
” Past studies have shown that women’s risk of developing AD more frequently than men do,” according to research conducted on APOE4. The present study focused on cellular activities that occur when females are simultaneously exposed to APOE4 and a version of the TREM2 dna, which also raises AD risk. It has been questionable how the specific variants contribute to a risk to the disease because the proteins that these genes encode include a variety of features in cells.
” Although these are two of the strongest risk factors for AD, much is known about how they improve disease risk and they have not been frequently studied up,” said top author , Dr. Li Gan, director of the , Helen and Robert Appel Alzheimer’s Disease Research Institute , and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the , Feil Family Brain and Mind Research Institute , at Weill Cornell Medicine.
Our intention was to combine these risk factors to show which pathways are altered when the risk of disease is highest.
Dr. Gan and her team, including lead author Dr. Gillian , Carling, a graduate student in the Weill Cornell Medicine Graduate School of Medical Sciences at the time of the study, established mouse models for AD carrying human versions of APOE4 and TREM2 R47H, a rare variant that increases AD risk 2-4.5-fold.
A mutation that is prevalent in AD brains and closely linked to cognitive decline in patients caused the mice to carry the mutation. To understand how these genetic variations had an impact on brain health, the team examined the mice at 9 to 10 months old, roughly the same age as middle age in humans.
They found that female, but not male, mice with both APOE4 and TREM2 R47H exhibited significant damage to the brain region that plays an important role in thinking and memory. In comparison to mice without these gene combinations, these mice had more severe tau protein clumps.
The researchers attributed the damage in these female brains to the brain’s immune cells, called microglia. Normally, microglia protect the brain, but in this case, they became” senescent”, referring to aged cells that lost their ability to function properly.
These aged microglia linger around and release inflammatory chemicals through a pathway known as cGAS-STING, rather than repairing damaged cells and protein clumps. Notably, the study discovered that female mice had more of these harmful effects, which is in line with reports that APOE4 poses a greater risk for women than men.
 ” ,Our research showed that when the two Alzheimer’s risk factors are combined in females with tau aggregates, the cGAS-STING pathway becomes highly activated,” Dr. Carling said. Repressing this deleterious pathway prevented the aging phenotype in microglia by lowering harmful inflammatory factors.
According to the researchers, the study emphasizes the need to take into account sex differences in Alzheimer’s research and treatment because the disease may progress differently between men and women, necessitates different treatment options, according to Dr. Gan.
By identifying the role of immune pathways like cGAS-STING in the progression of Alzheimer’s, particularly in individuals with high-risk genetic variants, the researchers hope to open the door to new strategies for treatment—and potentially prevention.
Funding: This work was supported by the National Institute on Aging, part of the National Institutes of Health, through grant numbers R01AG076448, R01AG072758, R01AG054214, R01AG074541, R01AG064239, K99AG078493, and F31AG079560.
About this genetics, neurology, and inflammation research news
Author: Krystle Lopez
Source: Weill Cornell University
Contact: Krystle Lopez – Weill Cornell University
Image: The image is credited to Neuroscience News
Original Research: Open access.
By Li Gan and al.,” Alzheimer’s disease-linked risk alleles increase microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.” Neuron
Abstract
Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
The strongest risk factors for late-onset sporadic Alzheimer’s disease ( AD ) include the ε4 allele of apolipoprotein E ( APOE), the , R47H , variant of triggering receptor expressed on myeloid cells 2 ( TREM2 ), and female sex.
Here, we combine , APOE4 , and , TREM2R47H , ( R47H) in female , P301S , tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms.
We find that , R47H , induces neurodegeneration in 9- to 10-month-old female , APOE4 , tauopathy mice.
The combination of , APOE4 , and , R47H , ( APOE4–R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate ( GMP ) -AMP synthase (cGAS ) -stimulator of interferon genes (STING ) signaling and downstream interferon response.  ,
APOE4-R47H , microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis.
Our study highlights cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk by uncovering pathways that are enhanced by the strongest AD risk factors.
