Novel truncated RNAs from jumping DNA encode reverse transcriptases in aging human brain

(Press-News.org) Alzheimer’s disease is the most common cause of dementia and affects more than a tenth of Americans aged 65 and older. The disease has proven difficult to develop new treatments for, and available treatment options are limited. With cases in the U.S. projected to more than double by 2050, more therapies are needed to improve patients’ quality of life and reduce the burden on the health care system and family caregivers.  

Scientists at Sanford Burnham Prebys and elsewhere have recently reported real-world links in medical records associating common HIV drugs with a reduced incidence of Alzheimer’s disease. The studies showed patients were at less risk of developing Alzheimer’s disease if they were taking drugs to block a famous enzyme called reverse transcriptase (RT), which copies RNA into DNA, opposite to the classical process. RT is best known from being an essential enzyme allowing HIV and other retroviruses to replicate in host cells, and FDA-approved RT inhibitor drugs prevent HIV reproduction.  

To better understand the links between Alzheimer’s disease risk and people taking prescribed RT inhibitor drugs, Jerold Chun, MD, PhD, and colleagues at Sanford Burnham Prebys looked for evidence of actual RT activity in the aging human brain and in brains affected by Alzheimer’s disease, identifying RT enzymatic activity, and novel RNAs that encode brain RTs especially in neurons of the aging human brain. The results were published online May 14, 2025, in The Journal of Neuroscience.

The Chun lab’s prior landmark publication in Nature in 2018 described how RT-mediated somatic gene recombination of the amyloid-beta precursor protein (APP) gene can occur in neurons of the human brain including those from the most common non-familial or sporadic form of Alzheimer’s disease. Rare familial mutations in the APP gene cause a form of Alzheimer’s disease that can be inherited in families, whereas sporadic disease lacks this inheritance but can be affected by non-inherited “somatic” mutations produced by RT.

“We asked a basic question: is there actually any RT activity in the aging human brain?” said Chun, a professor in the Center for Neurologic Diseases at the institute and the senior and corresponding author of the manuscript. “And, if there is, where does it come from and which brain cells are affected?”

The scientists examined post-mortem brain tissue from donors who had died from Alzheimer’s disease and compared it to control samples without obvious disease. RT activity was found within every brain sample, with a trend towards reductions in RT activity in the brains from terminal Alzheimer’s disease. This is consistent with the neuronal degeneration that is a hallmark of Alzheimer’s disease.

To investigate the origins of this RT activity further, the scientists assessed multiple possible sources and identified long interspersed nuclear element-1 (LINE1), an ancient genetic sequence so common in mammalian genomes that it makes up nearly one-fifth of all human DNA. It is normally inactive, but scientists have found rare forms that are active, using their own RTs to copy and paste themselves elsewhere in the genome.    

“The prevailing thought has been that LINE1 can only function if expressed from an intact, bicistronic mRNA copy,” said Juliet Nicodemus, an MD-PhD student working in the Chun lab as part of the Medical Scientist Training Program at the University of California San Diego and first author of the study. “Instead, through the use of long-read sequencing of Alzheimer’s disease brains and normal brains, we found thousands of truncated versions of LINE1 expressed in the human brain, including hundreds of sequences not annotated in the human genome.”

In addition to uncovering abbreviated versions of LINE1, the scientists found that most of these variations contained only one of the two protein-coding regions that appear on a full-length transcript.

“We demonstrated that these shortened sequences with a single coding region, or ‘monocistronic’ transcripts, are capable of encoding reverse transcriptase activity,” said Chun. “The level of activity from sequence to sequence also varied dramatically amongst variants, beyond 50X.”

The scientists addressed their second major question regarding the types of cells with RT activity by comparing samples of neuron-rich gray matter with white matter that contains mostly glial cells.

“RT activity was significantly higher in gray matter,” said Nicodemus. “This is consistent with RT activity being predominantly found in neurons and has potentially widespread implications as our post-mitotic neurons accumulate DNA changes over an individual’s lifetime.”

“We need to continue learning more about the different versions of reverse transcriptase at work in the aging and especially Alzheimer’s disease brain,” added Chun. “This will allow more targeted treatments to be developed in the future.”

Given the proven safety of FDA-approved RT inhibitor drugs, Chun also suggests that physicians and scientists should pursue prospective clinical trials studying these drugs’ effects on persons with early Alzheimer’s disease as a near-term approach to helping Alzheimer’s disease patients and their families.

Additional authors include Christine S. Liu, Linnea Ransom, Valerie Tan, William Romanow and Natalia Jimenez from Sanford Burnham Prebys.

The study was supported by the National Institutes of Health and National Institute on Aging (R01AG065541, R01AG071465, T32GM007198-42S1 and R01AG065541-02/03S1), The Bruce Ford & Anne Smith Bundy Foundation and the Larry L. Hillblom Foundation.

The study’s DOI is 10.1523/JNEUROSCI.2298-24.2025.

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