Summary: An inflammatory trigger similar to those produced during viral infections is elevated in the brains of people with Alzheimer’s disease and progressive supranuclear palsy (PSP).
Source: UT San Antonio
Researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) report that an inflammation-inducing molecule, resembling what cells produce during viral infections, is increased in Alzheimer’s disease and in progressive supranuclear palsy, a less common neurodegenerative disorder.
“We have identified a previously unrecognized trigger of brain inflammation in these conditions,” said Elizabeth Ochoa, lead author of the study and a recent doctoral graduate of UT Health San Antonio.
Published in Science Advances, the study describes how toxic forms of the protein tau—hallmarks of Alzheimer’s disease and PSP—activate so-called “jumping genes” or transposable elements. These sequences can relocate within the genome and, when activated by pathogenic tau, produce double-stranded RNA (dsRNA). This dsRNA resembles viral genetic material and can therefore stimulate an immune response in the brain.
“Transposable elements are an emerging area of interest in Alzheimer’s research,” Ochoa said. “Our data show that, beyond their ability to move within the genome, these elements create double-stranded RNA molecules that appear to trigger innate immune pathways. To the brain’s immune sensors, these RNAs look like viral infection even though they originate from our own genome.”
The investigators detected elevated levels of double-stranded RNA in postmortem brain tissue from people with Alzheimer’s disease and PSP, and they observed similar accumulations in mouse and Drosophila (fruit fly) models engineered to express pathogenic tau. These findings link tau pathology with activation of transposable elements and accumulation of inflammatory RNA species in the brain.
Bess Frost, Ph.D., senior author on the study, highlighted the role of astrocytes—supportive glial cells that regulate metabolism, neurotransmitters and blood-brain barrier function. “We observed substantial deposits of double-stranded RNA within astrocytes,” Frost said. “Astrocytes respond to aging and neuronal stress by changing their behavior, and our results suggest they may be central to controlling transposable element activity and the resulting inflammation.”
Progressive loss of neurons is a defining feature of Alzheimer’s and many other neurodegenerative diseases. To explore causality and mechanism, the team used fruit fly models to rapidly test how tau-driven changes lead to dsRNA formation and inflammation. They then confirmed relevance to mammals by examining tau transgenic mice and human postmortem brain tissue.
The authors report that specific retrotransposons activated by pathogenic tau form double-stranded RNA, and that heterochromatin decondensation—a disruption of normal chromatin structure driven by toxic tau—is a key upstream event. These dsRNA molecules and the cellular machinery that senses them were elevated in astrocytes from affected brains, implicating dsRNA-mediated innate immune activation in tau-related neurodegeneration.
“Understanding the full set of toxic molecules produced by activated transposable elements is critical,” Frost said. “We are already testing strategies to limit jumping gene activation in a Phase II clinical trial for Alzheimer’s disease, so characterizing all resulting toxic species, including double-stranded RNAs, will help guide therapeutic approaches.”
Ochoa earned her Ph.D. in the Cell Biology, Genetics and Molecular Medicine discipline of the Integrated Biomedical Sciences program at UT Health San Antonio, after completing her undergraduate studies at Seattle University. Frost is an associate professor of cell systems and anatomy and holds the Bartell Zachry Distinguished Professorship for Research in Neurodegenerative Disorders. Her work has been recognized with the Edith and Peter O’Donnell Award in Medicine and the 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
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Original Research: Open access. “Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation” by Elizabeth Ochoa et al., published in Science Advances.
Abstract
Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
Aggregation of abnormal tau protein in the brain defines a group of disorders known as tauopathies, which include Alzheimer’s disease. Prior studies have shown that pathogenic tau disrupts nuclear and genomic organization, leading to heterochromatin relaxation and activation of retrotransposons. Because retrotransposons resemble retroviruses, their activation can generate toxic intermediates—among them double-stranded RNA (dsRNA)—that provoke inflammatory responses.
In this work, the authors report increased levels of dsRNA and components of dsRNA-sensing pathways in astrocytes from postmortem brains of people with Alzheimer’s disease and PSP, as well as in tau transgenic mice. Using a Drosophila model of tauopathy, the study identifies specific retrotransposons that produce dsRNA and demonstrates that pathogenic tau and heterochromatin decondensation drive dsRNA-mediated neurodegeneration and neuroinflammation.
These findings support a model in which tau-induced chromatin changes and retrotransposon activation lead to elevated inflammatory transposable element–derived dsRNA in the adult brain, linking genomic instability to innate immune activation in neurodegenerative disease.