Summary: A new study reveals epigenetic alterations in the immune system of Alzheimer’s patients’ blood, suggesting environmental or behavioral factors could influence Alzheimer’s risk. The study indicates these epigenetic changes affect genes associated with Alzheimer’s susceptibility, potentially due to factors like viral infections or pollutants.
Investigating the peripheral immune system, the research team discovered that every immune cell type in Alzheimer’s patients shows signs of epigenetic modification. This novel finding opens the door to targeting specific genes for therapy and underscores the importance of considering the peripheral immune system’s role in Alzheimer’s disease progression.
Key Facts:
- Epigenetic changes in Alzheimer’s patients’ blood immune cells could be linked to environmental factors, altering genes related to Alzheimer’s risk.
- The study highlights the peripheral immune system’s involvement in Alzheimer’s, with T cells possibly entering the brain in response to damage signals.
- This research identifies potential therapeutic targets within the peripheral immune system, offering new avenues for Alzheimer’s treatment.
Source: Northwestern University
A new Northwestern Medicine study has found the immune system in the blood of Alzheimer’s patients is epigenetically altered. That means the patients’ behavior or environment has caused changes that affect the way their genes work.
Many of these altered immune genes are the same ones that increase an individual’s risk for Alzheimer’s. Northwestern scientists theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors.
“It is possible that these findings implicate the peripheral immune response in Alzheimer’s disease risk,” said lead investigator David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine. “We haven’t yet untangled whether these changes are reflective of brain pathology or whether they precipitate the disease.”
The study was published Feb. 9 in Neuron.
Previous research showed that many of the mutated genes putting a person at higher risk for Alzheimer’s are in the immune system. But scientists primarily studied the central immune system in the brain because Alzheimer’s is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.
Gate decided to study the blood. He and colleagues discovered every immune cell type in Alzheimer’s patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open — or exposed — the cells’ genome is vulnerable to alterations.
Then, Gate examined which genes are more open in these immune cells. He discovered that a receptor — CXCR3 — on the T cells was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally 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 said.
“T cells can be very toxic in the brain, but we also don’t know if these cells might be attempting to repair the damage in the brain,” Gate said.
Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.
“Altogether, these findings indicate that immune function in Alzheimer’s patients is significantly altered,” Gate said. “It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes.”
The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. Next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets.
Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst.
The title of the article is “Epigenetic dysregulation in Alzheimer’s disease peripheral immunity.”
Funding: The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging grant AG078713, both of the National Institutes of Health, Bright Focus Foundation, Alzheimer’s Association and Cure Alzheimer’s Fund.
About this Alzheimer’s disease research news
Author: Marla Paul
Source: Northwestern University
Contact: Marla Paul – Northwestern University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Epigenetic dysregulation in Alzheimer’s disease peripheral immunity” by David Gate et al. Neuron
Abstract
Epigenetic dysregulation in Alzheimer’s disease peripheral immunity
Highlights
- AD peripheral immune cells have more open chromatin
- AD CD8 T cells have a chromatin modification associated with expression of CXCR3
- AD monocytes have APOE genotype-specific chromatin modifications
- Genes associated with sporadic AD are altered at the chromatin level
Summary
The 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.
