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An inflammatory trigger is a new insight into Alzheimer’s disease and PSP

An inflammatory trigger is a new insight into Alzheimer’s disease and PSP

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Summary: An inflammatory trigger such as that present during viral infections is elevated in those with Alzheimer’s disease and progressive supranuclear palsy (PSP).

source: UT San Antonio

Scientists at the University of Texas Health Science Center at San Antonio (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 trigger of brain inflammation in these disorders,” said study author Elizabeth Ochoa of UT Health San Antonio.

The finding published in Scientific progress is new for that reason, she said.

Ochoa, a recent Ph.D. graduate, and her mentor, Dr. Bess Frost, the study’s senior author, are researchers in the Sam and Ann Barshop Institute on Longevity and Aging, the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, and the Department of Cellular Systems and Anatomy at UT Health San Antonio. Frost is the Bartell Zachry Distinguished Professor for the Study of Neurodegenerative Disorders.

Alzheimer’s disease and progressive supranuclear palsy are characterized by toxic deposits of a protein called tau. Their research found that tau-induced “jump genes”—which can be moved or copied to other locations in the genome—form double-stranded RNA. This abnormal RNA mimics the inflammatory trigger that is 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 can drive the disease process in addition to their ability to jump,” said Ochoa. “These double-stranded RNAs look like a virus to the immune system, even though the jumping genes are part of our normal genome.”

Alzheimer’s disease and progressive supranuclear palsy are characterized by toxic deposits of a protein called tau. Image is in the public domain

The researchers found an accumulation of double-stranded RNA in postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in the brains of mice and fruit fly models of tauopathy.

“We found significant deposits of double-stranded RNA in astrocytes, which are cells that provide metabolic support for neurons, regulate neurotransmitters and maintain the integrity of the blood-brain barrier,” Frost said. “In aging and disease, astrocytes respond to injury and disruption of 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 and other neurodegenerative diseases.

The researchers conducted experiments with fruit flies 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 was related to the mammalian disease, we also studied brain tissue from mouse models and from postmortem human brains affected by tauopathy,” Ochoa said.

“As we are currently targeting hopping gene activation in a local phase II clinical trial for Alzheimer’s patients, it is important to understand the full repertoire of toxic molecules, including double-stranded RNAs, that the hopping genes produce,” said Frost.

Ochoa recently earned his Ph.D. from the Cell Biology, Genetics and Molecular Medicine discipline of the Integrated Biomedical Sciences program at UT Health San Antonio. She received her BA from Seattle University.

Frost, associate professor of cellular systems and anatomy in the Barshop and Biggs Institutes at UT Health San Antonio, received the highly competitive 2020 Edith and Peter O’Donnell Award in Medicine from TAMEST, the Texas Academy of Medicine, Engineering, Science and Technology. She was also a gold medalist in 2022 for the prestigious Oscar Fischer Award.

About this Alzheimer’s and PSP research news

Author: Press office
source: UT San Antonio
Contact: Press Office – UT San Antonio
Image: Image is in the public domain

See also

An inflammatory trigger is a new insight into Alzheimer’s disease and PSP

Original Research: Free access.
Pathogenic tau-induced dsRNA derived from a transposable element induces neuroinflammation” by Elizabeth Ochoa et al. Scientific progress


Summary

Pathogenic tau-induced dsRNA derived from a transposable element induces neuroinflammation

The deposition of tau protein aggregates in the brains of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various tauopathy model systems have reported that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau-induced decondensation of heterochromatin and subsequent retrotransposon activation as a causative mediator of neurodegeneration.

Based on their similarity to retroviruses, retrotransposons induce neuroinflammation through toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and the dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from 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 causes causally dsRNA-mediated neurodegeneration and neuroinflammation.

Our study suggests that pathogenic tau-induced heterochromatin decondensation and retrotransposon activation cause an increase in transposable element-derived inflammatory dsRNA in the adult brain.


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