Summary: FDA-approved HIV drugs targeting reverse
transcriptase (RT) may reduce Alzheimer’s risk by blocking similar
enzymatic activity in the aging brain. Scientists discovered unexpected
RT activity in neurons of healthy and Alzheimer’s brains, tracing it to
truncated LINE1 elements—ancient genetic sequences capable of copying
themselves via RT.
These monocistronic LINE1 fragments were
especially active in gray matter, where neurons reside and accumulate
mutations over time. The findings suggest that existing RT inhibitors
could be repurposed in clinical trials to help slow or prevent
Alzheimer’s disease progression.
Key Facts:
- Unexpected Brain RT Activity: Reverse transcriptase activity was found in neurons, especially in aging and Alzheimer’s-affected brains.
- LINE1 Variants Identified: Thousands of previously unannotated, truncated LINE1 transcripts were found to encode RT.
- Therapeutic Potential: FDA-approved HIV RT inhibitors may be repurposed for Alzheimer’s treatment through clinical trials.
Source: Sanford Burnham Prebys
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.
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. Credit: Neuroscience News
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.
Funding: 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.
About this neuropharmacology and Alzheimer’s disease research news
Author: Greg Calhoun
Source: Sanford Burnham Prebys
Contact: Greg Calhoun – Sanford Burnham Prebys
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Sequence
diversity and encoded enzymatic differences of monocistronic L1 ORF2
mRNA variants in the aged normal and Alzheimer’s disease brain” by Jerold Chun et al. Journal of Neuroscience
