Reverse transcriptase activity found in aging and Alzheimer’s brains

Alzheimer’s disease is the most common cause of dementia and affects more than one tenth of Americans aged 65 and older. The disease has proved difficult to develop new treatments for and available treatment options are limited. With cases in the US that will be more than double in 2050, more therapies are needed to improve the quality of life of patients and to reduce the burden on the health care system and caregivers.

Scientists from Sanford Burnham Prebys and elsewhere have recently reported real ties in medical records that associate common HIV drugs with a reduced incidence of Alzheimer’s disease. The studies showed that patients were less at risk of developing Alzheimer’s disease if they used medicines to block a famous enzyme called reverse transcriptase (RT), which copies RNA in DNA, towards the classic process. RT is best known for an essential enzyme that allows HIV and other retroviruses to replicate in host cells, and HIV reproduction approved by the FDA.

In order to better understand the connections between Alzheimer’s health insurance and people who use prescribed RT -inhibitor medicines, they searched better at Sanford Burnham Preby’s in search of proof of the older brains of the people of Sanford Burnham’s disease. The results were published online on May 14, 2025, in The Journal of Neuroscience.

The earlier historical publication of the Chun Lab in Nature In 2018, it described how RT-mediated somatic genrecombination of the amyloid-beta forest protein (app) can occur in neurons of the human brain, including those of the most common non-cozy or sporadic form of Alzheimer’s disease. Rare family mutations in the app gene cause a form of Alzheimer’s disease that can be inherited in families, while sporadic disease is missing this inheritance but can be influenced by non-light “somatic” mutations produced by RT.

“We have asked a basic question: is there actually some RT activity in the aging human brain?” said Chun, a professor in the Center for Neurological Diseases at the Institute and the Senior and accompanying author of the manuscript. “And, if that is, where does it come from and which brain cells are influenced?”

The scientists investigated post-mortem brain tissue of donors who died of Alzheimer’s disease and compared it with control monsters without a clear disease. RT activity was found within every brain sample, with a trend to reducing RT activity in the brain of Terminal Alzheimer’s disease. This is consistent with the neuronal degeneration that is a characteristic of Alzheimer’s disease.

In order to further investigate the origin of this RT activity, the scientists assessed several possible sources and identified for a long time alternating nuclear element-1 (Line1), an old genetic sequence that is so common in mammals that it is almost a 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 elsewhere in the genome.

“The prevailing thought is that Line1 can only function if it is expressed from an intact, bicistronic mrna copy,” said Juliet Nicodemus, an MD-PHD student who works in the Chun Lab as part of the training program for medical scientist at the University of California San Diego and first author. “Instead, by the use of long -read sequencing of the brain of Alzheimer’s disease and normal brain, we found thousands of troubled versions of Line1 to expression brought into the human brain, including hundreds of sequences that are not annotated in the human genome.”

In addition to exposing abbreviated versions of Line1, the scientists found that most of these variations contain only one of the two protein -coding areas that appear on a transcript of the entire length.

We have shown that these shortened sequences with a single coding area or ‘monocstronic’ transcripts are capable of coding for reverse transcriptase activity. The activity level from sequence to sequence also varied dramatically between variants, beyond 50x. “

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

The scientists discussed their second important question about the types of cells with RT activity by comparing samples of neuron-rich gray matter with white matter that mainly contains glial cells.

“RT activity was considerably higher in gray matter,” said Nicodemus. “This is consistent with RT activity that is mainly found in neurons and possibly has widespread implications because our post-mitotic neurons collect DNA changes during the life of an individual.”

“We need to learn more about the different versions of Reverse Transcriptase at work in the aging and especially the brains of Alzheimer’s disease,” Chun added. “This allows more targeted treatments to be developed in the future.”

Given the proven safety of RT inhibitor-approved by the FDA, Chun also suggests that doctors and scientists must strive for prospective clinical studies to study the effects of these drugs on people with the early Alzheimer’s disease as an near-term approach to help Alzheimer’s disease patients and their families.