Reverse transcriptase activity in aging and Alzheimer's brains

Reverse transcriptase activity in aging and Alzheimer's brains

Alzheimer's disease is the most common cause of dementia, affecting more than a tenth of Americans ages 65 and older. The disease has proven difficult to develop new treatments for and available treatment options are limited. Projected to more than double by 2050 in the United States, more therapies are needed to improve patients' quality of life and reduce the burden on the healthcare system and family caregivers.

Scientists at Sanford Burnham Prebys and elsewhere have recently reported real-world links in medical records linking common HIV drugs to reduced incidence of Alzheimer's disease. The studies showed that patients had a lower risk of developing Alzheimer's disease when they took drugs to block a famous enzyme called reverse transcriptase (RT), which copies RNA into DNA, versus the classic process. RT is best known for being an essential enzyme that allows 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 enzymatics and novel human. The results were published online on May 14, 2025, inThe Journal of Neuroscience.

The previous landmark of the Chun Laboratory inNatureIn 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, while sporadic diseases lack this inheritance but can be influenced by unheard of "somatic" mutations produced by RT.

“We asked a fundamental question: Is there actually RT activity in the aging human brain?” said Chun, a professor in the Center for Neurological 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 of Alzheimer's disease and compared it to control samples with no apparent disease. RT activity was found in each brain sample, with a trend of decreasing RT activity in brains from terminal Alzheimer's disease. This is consistent with the neuronal degeneration that is a hallmark of Alzheimer's disease.

To further investigate the origins of this RT activity, the scientists evaluated several possible sources and identified long-intermediate nuclear element-1 (lineage 1), an ancient genetic sequence so common in mammalian genomes that it accounts for nearly a fifth of all human DNA. It is normally inactive, but scientists have found rare forms that are active and use their own RTs to copy and paste themselves elsewhere in the genome.

“The prevailing thought has been that Line1 can only function when expressed from an intact, bicistronic mRNA copy,” said Julia Nicodemus, an MD-PhD student who worked 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, by using long-lived sequencing of Alzheimer's disease and normal brains, we found thousands of truncated versions of line1 expressed in the human brain, including hundreds of sequences that are unannotated in the human genome."

In addition to uncovering the abbreviated versions of lineage 1, the scientists found that most of these variations contained only one of the two protein coding regions that appear in a full-length transcript.

We have shown that these truncated sequences with a single coding region or “monokistronic” transcripts are capable of encoding reverse transcriptase activity. The activity level from sequence to sequence also varied dramatically between variants, beyond 50x. “

Jerold Chun, MD, PhD, Professor, Center for Neurological Diseases, Sanford Burnham Prebys

The scientists addressed their second main question about the types of cells with RT activity by comparing samples of neuron-rich gray matter with white matter, which contains mostly glial cells.

“RT activity was significantly higher in gray matter,” said Nicodemus. “This is consistent with RT activity found predominantly in neurons and may have widespread implications as our post-mitotic neurons accumulate DNA changes over the lifespan of an individual.”

“We need to continue to learn more about the different versions of reverse transcriptase in aging and particularly in the Alzheimer's brain,” Chun added. “In this way, more targeted treatments can be developed in the future.”

Given the proven safety of FDA-approved RT inhibitor drugs, Chun also suggests that physicians and scientists should conduct prospective clinical trials that examine the effects of these drugs on individuals with early Alzheimer's disease in the short term to support Alzheimer's disease patients and their families.

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