Summary: A recent study has found that there are genetic changes in the immune system of Alzheimer’s patients’ blood. These changes could be influenced by environmental or behavioral factors and may affect the risk of developing Alzheimer’s disease. The study suggests that these genetic changes impact genes linked to Alzheimer’s susceptibility, possibly due to factors like viral infections or exposure to pollutants. By examining the peripheral immune system, the research team discovered that all types of immune cells in Alzheimer’s patients show signs of genetic modification. This new discovery suggests potential targets for therapy and emphasizes the importance of considering the role of the peripheral immune system in the progression of Alzheimer’s disease.Key Facts:Genetic changes in the immune cells of Alzheimer’s patients’ blood may be connected to environmental factors, altering genes related to Alzheimer’s risk. The study emphasizes the involvement of the peripheral immune system in Alzheimer’s, with T cells possibly entering the brain in response to signals of damage. This research identifies potential therapeutic targets within the peripheral immune system, offering new approaches for treating Alzheimer’s.Source: Northwestern UniversityA new study from Northwestern Medicine has revealed that the immune system in the blood of Alzheimer’s patients has undergone genetic alterations. This means that the behavior or environment of the patients has caused changes that affect the functioning of their genes. Many of these altered immune genes are the same ones that increase an individual’s risk for Alzheimer’s. Northwestern scientists believe that the cause of these changes could be a previous viral infection, exposure to environmental pollutants, or other lifestyle factors and behaviors.
This study was published on Feb. 9 in Neuron.A previous study showed that many of the mutated genes that increase a person’s risk for Alzheimer’s are related to the immune system. However, scientists mostly focused on the central immune system in the brain because Alzheimer’s is a brain disease. The immune system in the blood, also known as the peripheral immune system, has largely been overlooked. Lead investigator David Gate chose to study the blood. He and his colleagues discovered genetic changes in every type of immune cell in Alzheimer’s patients, as indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open, the cells’ genome is susceptible to changes.Gate then investigated which genes are more open in these immune cells and found that a receptor called CXCR3 on the T cells was more exposed. Gate believes CXCR3 acts like an antenna on T cells, allowing the cells to enter the brain. T cells do not typically enter the brain because they can cause inflammation.“The brain is emitting a signal that it is damaged, and the T cells are homing to that signal by their antenna, CXCR3,” Gate explained. “T cells can be very harmful in the brain, but we also don’t know if these cells might be attempting to repair the damage in the brain,” he added.Gate also found genetic changes in inflammatory proteins in white blood cells called monocytes.“Overall, these findings indicate that immune function in Alzheimer’s patients is significantly altered,” Gate stated. “It is possible that environmental factors, such as pollutants, or infections that a person has had during their lifetime, lead to these genetic changes.”The findings identified several genes that could serve as therapeutic targets for influencing the peripheral immune system. The next steps in the research involve preclinical studies using in vitro culture systems and animal models to test these targets.Other authors from Northwestern University include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova, and Lynn van Olst.The article is titled “Epigenetic dysregulation in Alzheimer’s disease peripheral immunity.”Funding: The research is supported by the National Institute of Neurological Disorders and Stroke grant NS112458 and the National Institute on Aging grant AG078713, both of the National Institutes of Health, as well as the Bright Focus Foundation, Alzheimer’s Association, and Cure Alzheimer’s Fund.About this Alzheimer’s disease research newsAuthor: Marla Paul
Source: Northwestern University
Contact: Marla Paul – Northwestern University
Image: The image is credited to Neuroscience NewsOriginal Research: Closed access.
“Epigenetic dysregulation in Alzheimer’s disease peripheral immunity” by David Gate et al. NeuronAbstractEpigenetic dysregulation in Alzheimer’s disease peripheral immunityHighlightsAD peripheral immune cells have more open chromatinAD CD8 T cells have a chromatin modification associated with expression of CXCR3AD monocytes have APOE genotype-specific chromatin modificationsGenes associated with sporadic AD are altered at the chromatin levelSummaryThe peripheral immune system in Alzheimer’s disease (AD) has not been thoroughly studied with modern sequencing methods. To investigate epigenetic and transcriptional alterations to the AD peripheral immune system, we used single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing.We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis-regulatory DNA element co-accessible with the CXC motif chemokine receptor 3 gene promoter.In monocytes, we identify a novel AD-specific RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype-dependent epigenetic changes in monocytes.Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD risk.Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in AD peripheral immunity.
