Alzheimer’s disease is the most common cause of dementia and affects more than one -tenth of Americans aged 65 or older. The disease has proven to be difficult to develop new treatments and the available treatment options are limited. In cases in the US projecting into overflow by 2050, more treatments are required to improve the quality of life of patients and reduce the burden of the healthcare system and family carers.
Scientists at Sanford Burnham Prebys and elsewhere have recently reported real world links to medical records connecting common HIV medicines with a reduced frequency of Alzheimer’s disease. Studies have shown that patients are at a lower risk of developing Alzheimer’s disease if they were taken to prevent a famous enzyme called reverse transcriptase (RT), which copies RNA to DNA, opposite the classic process. RT is best known than being a basic enzyme that allows HIV and other retroviruses to reproduce in host cells and FDA -approved RT inhibitors prevent HIV reproduction.
To better understand the links between the danger of Alzheimer’s disease and the people receiving prescription RT inhibitor drugs, Jerold Chun, MD, PhD and his Sanford Burnham Prebys seeking evidence Alzheimer’s, identifying the RT enzymatic activity. Results were published online on May 14, 2025, at The neuroscience magazine.
The previous post of Chun Lab’s Lab Nature 2018 described how it can occur in human brain neurons caused by the mediation of RT. Rare family mutations in the application gene cause a form of Alzheimer’s disease that can be inherited in families, while sporadic disease lacks this heritage, but may be affected by non -sealing “bodily” mutations produced by RT.
“We asked a basic question: Is there actually some RT activity in the aging human brain?” said Chun, professor at Center for Neurological Diseases at the Institute and the senior and corresponding author of the manuscript. “And, if any, where does it come from and what brain cells are affected?”
Scientists examined post -mortem brain tissue from donors who had died of Alzheimer’s disease and compare it to control samples without obvious illness. RT activity was found in every sample of the brain, with a tendency to reduce RT activity in brains by Terminal Alzheimer’s disease. This is in line with neuronal degeneration that is a characteristic feature of Alzheimer’s disease.
To further explore the origin of this RT activity, scientists evaluated multiple possible sources and identified long-term scattered nuclear elements (line1), an ancient genetic sequence so common in mammalian genomes that are almost one-fifth. They are usually 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 was that line1 could only work if expressed by an intact Bicistronic MRNA copy,” said Juliet Nicodemus, a MD-PhD student working at the Chun Lab as part of the Medical Scientist Training Program at the University of California in San Diego and the first author. “Instead, through the use of long reading of the brains of Alzheimer’s disease and normal brains, we have found thousands of truncated versions of the line1 expressed in the human brain, including hundreds of sequences that are not commented on in the human genre.”
In addition to revealing the abbreviated versions of the line1, scientists found that most of these variants contained only one of the two protein encoding areas that occur in a full transcription length.
We have shown that these abbreviated sequences with a single coding area or “singleocytes” transcripts are able to codify inverse transcription activity. The level of activity from sequence in sequence varies dramatically between variants, beyond 50x. ”
Jerold Chun, MD, PhD, Professor, Center for Neurological Diseases, Sanford Burnham Prebys
Scientists were about their second important question about RT -active cell types, comparing the samples of nerve -rich gray matter with white matter containing mainly global cells.
“The RT activity was significantly higher in gray matter,” Nicodemus said. “This is in accordance with the RT activity that is primarily in neurons and has potentially widespread effects as our post-mitistic neurons accumulate DNA changes during a person’s life.”
“We must continue to learn more about the various versions of the reverse transcriptase at work in aging and especially the brain of Alzheimer’s disease,” Chun added. “This will allow the development of more targeted treatments in the future.”
Given the proven safety of RT drugs approved by the FDA, Chun also suggests that doctors and scientists should follow future clinical trials studying the effects of these drugs on people with Alzheimer’s early disease as short -term approach to their patients with Alzheimer’s patients.
Source:
Magazine report:
Nicodemus, J., et al. (2025). The diversity of sequence and the encoded enzymatic differences of the MRNA variants of the L1 Orf2 monocle in the elderly normal and the brain of Alzheimer’s disease. Neuroscience newspaper. doi.org/10.1523/jneurosci.2298-24.2025.
