Summary: An inflammatory trigger like that present in viral infections is elevated in people with Alzheimer’s disease and progressive supranuclear palsy (PSP).
Source: UT San Antonio
Scientists from the University of Texas San Antonio Health Sciences Center (UT Health San Antonio) reported today that an inflammatory trigger like the one present during viral infections is elevated in Alzheimer’s disease. and progressive supranuclear palsy, a rare brain disorder.
“We have identified a new brain inflammation trigger in these disorders,” said study author Elizabeth Ochoa from UT Health San Antonio.
The finding published in science advances is new for this reason, she says.
Ochoa, a recent Ph.D. graduate, and her mentor, Bess Frost, Ph.D., lead author of the study, are researchers at the Sam and Ann Barshop Institute for Longevity and Aging Studies, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, and in the Department of Cellular Systems and Anatomy at UT Health San Antonio. Frost is the Bartell Zachry Professor Emeritus for Neurodegenerative Disorders Research.
Alzheimer’s disease and progressive supranuclear palsy are marked by toxic deposits of a protein called tau. Their research found that tau-induced “jumping genes” – which can move or copy to other places in the genome – form double-stranded RNA. This abnormal RNA mimics the inflammatory trigger also present in viral infections.
“Transposable elements – so-called jumping genes – are a new area of interest in understanding Alzheimer’s disease. Our study provides new insights into how they may drive the disease process in addition to their ability to jump,” Ochoa said. “These double-stranded RNAs look like a virus to the immune system, even though the jumping genes are part of our normal genome.”
The researchers detected an accumulation of double-stranded RNA in the postmortem brain tissue of patients with Alzheimer’s disease and progressive supranuclear palsy and in the brains of mice and Drosophila models of tauopathy.
“We found substantial deposits of double-stranded RNA in astrocytes, which are cells that provide metabolic support to neurons, regulate neurotransmitters, and maintain the integrity of the blood-brain barrier,” Frost said. In aging and disease, astrocytes respond to injury and disturbances in the neuronal environment. Our findings open new doors to understanding the biology of astrocytes and their role in the control of transposable elements.
The loss of neurons, which are cells of the central nervous system, is progressive in Alzheimer’s disease and other neurodegenerative diseases.
Researchers are conducting fruit fly experiments to quickly test their questions about double-stranded RNA and inflammation in the brain. “To ensure that what we found in our fruit fly experiments is relevant to mammalian diseases, we also studied brain tissue from mouse models and post-mortem human brains affected by tauopathy,” Ochoa said.
“As we are currently targeting the activation of jumping genes in a local phase II clinical trial for patients with Alzheimer’s disease, it is important to understand the full repertoire of toxic molecules, including double-stranded RNAs, that produce the jumping genes,” Frost said.
Ochoa recently obtained her doctorate. from the Cell Biology, Genetics, and Molecular Medicine discipline of the Integrated Biomedical Sciences program at UT Health San Antonio. She received her undergraduate degree from Seattle University.
Frost, an associate professor of cellular systems and anatomy at the Barshop and Biggs Institutes at UT Health San Antonio, received the highly competitive Edith and Peter O’Donnell Prize in Medicine in 2020 from TAMEST, the Texas Academy of Medicine, Engineering, Science and Technology. She was also a gold medalist in 2022 for the prestigious Oskar Fischer Prize.
About this Alzheimer’s disease and PSP research news
Author: Press office
Source: UT San Antonio
Contact: Press Office – UT San Antonio
Picture: Image is in public domain
See also
Original research: free access.
“Transposable element-derived dsRNA induced by pathogenic tau leads to neuroinflammationby Elizabeth Ochoa et al. science advances
Summary
Transposable element-derived dsRNA induced by pathogenic tau leads to neuroinflammation
The deposition of tau protein aggregates in the brains of affected individuals is a defining feature of ‘tauopathies’, including Alzheimer’s disease. Studies in human brain tissue and various tauopathy model systems report that toxic forms of tau adversely affect nuclear and genomic architecture, identifying pathogenic tau-induced heterochromatin decondensation and resultant retrotransposon activation as causative mediator of neurodegeneration.
Based on their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes from postmortem brain tissue of patients with Alzheimer’s disease and progressive supranuclear palsy and in the brains of tau transgenic mice.
Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic decondensation of tau and heterochromatin causally results in dsRNA-mediated neurodegeneration and neuroinflammation.
Our study suggests that pathogenic tau-induced heterochromatin decondensation and retrotransposon activation cause an elevation of dsRNA derived from inflammatory transposable elements in the adult brain.
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