Summary: FDA‑approved HIV reverse transcriptase inhibitors may lower Alzheimer’s risk by blocking a comparable enzyme active in the aging brain. Scientists have discovered unexpected RT activity in neurons from both healthy brains and Alzheimer’s patients. They attribute this activity to truncated LINE1 elements – ancient gene sequences that can replicate themselves via RT.
These monocistronic LINE1 fragments were active primarily in gray matter, where neurons are located, and mutations accumulate over time. The results suggest that current RT inhibitors could be used in clinical trials to slow or stop the progression of Alzheimer’s disease.
Important facts:
- Unexpected RT activity of the brain:Reverse transcriptase activity has been detected in neurons in the brains of people with Alzheimer’s disease, especially in older brains.
- Identified LINE1 Variants: Thousands of previously unknown truncated LINE1 transcripts encoding reverse transcriptase have been found.
- Treatment potential:FDA-approved HIV RT inhibitors could be repurposed in clinical trials to treat Alzheimer’s disease.
Source: Sanford Burnham Prebys
Alzheimer’s disease is the most common cause of dementia, affecting one-tenth of all Americans over the age of 65. Developing new treatments for the disease has proven difficult, and available treatment options are limited.
Therefore, more treatments are needed to improve the quality of life of patients and reduce the burden on healthcare providers and caregivers. Scientists at Sanford Burnham Prebys and other institutions recently discovered a link in medical records between common HIV medications and lower incidences of Alzheimer’s disease.
RT is known to be a key enzyme that enables HIV and other retroviruses to replicate in host cells. FDA-approved RT inhibitors block HIV replication. To better understand the links between Alzheimer’s risk and the use of prescription drugs that block RT activity, Dr. Jerrold Chun and his colleagues at Sanford Burnham-Prebys Hospital looked for evidence of actual RT activity in the aging human brain and in brains affected by Alzheimer’s disease. They identified activity of RT enzymes and novel RNAs encoding RTs in the brain, specifically in neurons of the aging human brain.
The findings were published online in the Journal of Neuroscience on May 14, 2025. They build on the Chun lab’s landmark 2018 Nature study, which revealed that reverse transcriptase (RT)–mediated somatic genetic recombination of the amyloid‑beta precursor protein (APP) gene can occur in human brain neurons — including those affected by the more common, non‑familial (sporadic) form of Alzheimer’s disease.
Rare familial mutations in the APP gene cause a form of Alzheimer’s disease that can run in families, while sporadic forms of the disease do not exhibit this inheritance but may be affected by non-inherited “somatic” changes caused by RT. “We posed a fundamental question: Is reverse transcriptase activity truly present in the aging human brain?” said Chun, professor in the institute’s Center for Neurological Diseases and lead author of the study. “If it is, we want to know its source — and which brain cells it impacts.”
The scientists examined postmortem brain tissue from donors who died of Alzheimer’s disease and compared it to samples from controls without the disease. RT activity was detected in all of the brain samples, with a trend toward decreased RT activity in brains in the late stages of Alzheimer’s disease. This is consistent with the neuronal degeneration characteristic of Alzheimer’s disease.
To further investigate the source of this RT activity, the scientists examined several potential sources and identified long-interspersed nuclear element 1 (LINE1), an ancient gene sequence so abundant in mammalian genomes that it makes up about a fifth of human DNA. Normally inactive, the scientists found rare, active forms that use their RTs to replicate elsewhere in the genome.
“The current theory is that LINE1 can only function when expressed from a conserved bicistronic mRNA copy,” said Juliette Nicodemus, a doctoral student working in Chun’s lab as part of the UC San Diego Medical Scientist Training Program.
“Instead, using long-read sequences from Alzheimer’s patients and normal brains, we found thousands of truncated versions of LINE1 expressed in the human brain, including hundreds of untranslated sequences in the human genome.” The scientists not only discovered truncated versions of LINE1, but also found that in most of these mutations, only one of the two protein-coding regions is found in the full-length transcript.
“We showed that these truncated sequences with a single coding region, called monocistronic transcripts, are capable of encoding reverse transcriptase activity,” Chen said. “The level of activity between sequences also varies dramatically between different conditions, by a factor of 50.”
The scientists answered their second key question about the types of cells with RT activity by comparing samples of neuron-rich gray matter with white matter, which is composed primarily of glial cells. Nicodemus said that RT activity was significantly higher in gray matter. “This is consistent with the fact that RT activity occurs primarily in neurons and may have far-reaching effects, as our post-mitotic neurons continue to accumulate DNA changes throughout life.”
“We need to learn more about the different versions of reverse transcriptase that are active in the aging brain, especially in Alzheimer’s patients,” Chen added. “This will allow us to develop more targeted treatments in the future.” Given the proven safety of FDA-approved RT inhibitors, Chun also recommends that doctors and scientists conduct prospective clinical trials to study the effects of these drugs in people with early-stage Alzheimer’s disease. This could be a short-term way to help Alzheimer’s patients and their families.
Other authors include Christine S. Liu, Linnea Ransom, Valerie Tan, William Romano, and Natalia Jimenez of Sanford Burnham Prebison.
Funding: This research was supported by the National Institutes of Health and the National Institute on Aging (R01AG065541, R01AG071465, T32GM007198-42S1 and R01AG065541-02/03S1), the Bruce Ford and Ann Smith Bundy Foundation and Hillblo ML.
Abstract
Sequence diversity and encoded enzyme differences of monocistronic L1 ORF2 mRNA variants in normal and Alzheimer’s brains
Reverse transcriptase (RT) activity in the human brain has been linked to somatic retroinsertion/retrotransposition. However, the endogenous enzymatic functions involved and their original sources remain unclear. L1 retrotransposons (LINE-1) express bicistronic ORF2, which contains RT and endonuclease (EN) domains, as well as RNA-binding protein ORF1, which together facilitate L1 retrotransposition and contribute to somatic genomic mosaicism (SGM).
Here, we investigated the diversity of cerebral cortex patterns of endogenous RT activities and L1 mRNA from 31 brains with and without Alzheimer’s disease (both sexes).
Analysis of brain tissue revealed that full‑length bicistronic L1 transcripts were almost entirely absent, representing less than 0.01% of all detected L1 sequences, with the majority of these being noncoding. In contrast, single‑gene (monocistronic) transcripts for ORF1 and ORF2 were consistently present across all samples. Spatial transcriptomic mapping showed that these two genes are expressed at different levels within neurons. Reverse transcriptase (RT) activity was measurable in every brain examined, though it was reduced in Alzheimer’s disease (AD) cases — a finding in line with the loss of neurons seen in advanced AD. RT activity was more pronounced in gray matter and closely tracked with neuronal ORF2 expression, pointing to neurons as a key source.
The team also cataloged over 550 distinct protein‑coding ORF2 variants with poly(A) tails — more than double the number recorded in the human reference genome (hg38). Laboratory overexpression of both complete and truncated ORF2 forms led to a dramatic ~50‑fold rise in RT activity and a modest ~1.3‑fold increase in endonuclease (EN) activity. These results highlight the inherent functional capacity of monocistronic ORF2 variants in the brain. The remarkable diversity of these sequences could help explain variations in RT‑driven somatic gene repair or retroinsertion events, ultimately shaping the genomic mosaicism observed in both healthy and Alzheimer’s‑affected brains.
