Scientists at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) reported today that in Alzheimer’s disease and progressive supranuclear palsy, a rare brain disorder, Inflammation triggers are elevated.
“We’ve identified a new trigger for brain inflammation in these diseases,” said study author Elizabeth Ochoa, Ph.D., from UT Health San Antonio.The discovery was published in scientific progress For this reason it was novel, she said.
Ochoa is a recent Ph.D. graduate, and her advisor, Bess Frost, Ph.D., senior author of the study, is a member of the Sam and Ann Barshop Institute for Longevity and Aging, the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Disease and cell line researchers at UT Health San Antonio Systems and Anatomy. Frost is the Bartell Zachry Distinguished Professor of Neurodegenerative Disease Research.
Alzheimer’s disease and progressive supranuclear palsy are characterized by toxic deposits of a protein called tau. Their study found that tau-induced “jumping genes” — which can relocate or replicate themselves elsewhere in the genome — form double-stranded RNA. This abnormal RNA mimics inflammatory triggers that are also present in viral infections.
“Transposable elements — so-called jumping genes — are a new area of understanding of Alzheimer’s disease. Our study provides new insights into how they drive the disease process beyond their ability to jump,” Ochoa said. “These double-stranded RNAs look like viruses to the immune system, even though the jumping genes are part of our normal genome.”
The researchers detected accumulation of double-stranded RNA in the postmortem brain tissue of patients with Alzheimer’s disease and progressive supranuclear palsy, as well as in the brains of mouse and Drosophila tau disease models.
“We found large deposits of double-stranded RNA in astrocytes, 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 astrocyte biology and their role in the control of transposable elements .”
Loss of neurons (the cells of the central nervous system) is progressive in Alzheimer’s and other neurodegenerative diseases.
The researchers performed experiments in fruit flies to quickly test their questions about double-stranded RNA and brain inflammation. “To make sure that what we found in the fruit fly experiments was relevant to mammalian disease, we also studied brain tissue from mouse models and postmortem human brains affected by tau disease,” Ochoa said.
“Because we are currently targeting jumping gene activation in local Phase II clinical trials in Alzheimer’s disease patients, it is important to understand the repertoire of toxic molecules produced by jumping genes, including double-stranded RNA,” Frost said. Say.
Ochoa recently earned his Ph.D. in Cell Biology, Genetics and Molecular Medicine from UT Health San Antonio’s Integrative Biomedical Sciences program. She received her undergraduate degree from Seattle University.
Frost, associate professor of cellular systems and anatomy at UT Health San Antonio’s Barshop and Biggs Research Institute, received the highly competitive Edith and Peter O ‘Donnell Award for Medicine. She is also the 2022 Oscar Fischer Award Gold Medalist.
This research was supported by the National Institute of Neurological Disorders and Stroke, the Rain Foundation and the National Institute of General Medicine. Co-author Dr. Kevin Bieniek is director of the UT Health San Antonio Glenn Biggs Institute Brain Bank, which was supported by the National Institute on Aging, the Texas Alliance for Alzheimer’s Research and Care, Bill and Rebecca Reed Center for Precision Medicine with support from Bartell and the Mollie Zachry Foundation for Alzheimer’s Disease Research and Patient Care.
The Mayo Clinic Brain Bank provided human brain tissue. Co-author William Ray, PhD, of the Neurodegeneration Consortium in Therapeutic Discovery Division at The University of Texas MD Anderson Cancer Center, provided mouse brain tissue for analysis.