Medical Surprise: HIV Drugs May Protect Brain From Alzheimer's

Scientists have discovered that certain parts of our DNA, called LINE-1, can remain active in the brain even as we age. These parts can copy themselves and spread within the DNA, which can cause small changes in neurons. This happens in both healthy brains and brains with Alzheimer’s. Research shows that these changes can influence how the brain works and help us better understand aging and diseases like Alzheimer’s.

The human brain is made up of many different types of cells, connected in complex networks that allow it to function properly. Most of these cells are neurons, which no longer divide once they are formed.

Interestingly, scientists have discovered that even within the brain of a single person, neurons can have small differences in their DNA. These differences are called somatic genomic mosaicism, and they appear throughout life for a variety of reasons.

One of these causes is related to elements of our own DNA called retrotransposons, specifically LINE-1 (or L1). These elements work as a kind of genetic “copy and paste”: they can make copies of themselves and insert them into other places in the DNA, using an enzyme called reverse transcriptase (RT).

Reverse transcriptase is an enzyme used by some viruses, such as HIV, to convert their genetic material from RNA to DNA inside human cells, an essential step for the virus to integrate into the cell's DNA and begin replicating.

To prevent this crucial step, antiretroviral drugs used to treat HIV include reverse transcriptase inhibitors, which block the action of this enzyme and thus make it harder for the virus to multiply.

Interestingly, recent studies suggest that this same enzyme may also be involved in brain processes linked to aging and neurodegenerative diseases, such as Alzheimer's. Therefore, it is believed that drugs that inhibit reverse transcriptase, in addition to fighting HIV, may also have a protective effect on the brain.

Although the human genome contains about 500,000 copies of these L1s, most are inactive. However, a small portion is still functional, especially a subfamily called L1HS, which can continue to copy itself and spread throughout the DNA.

The problem is that this ability to "self-replicate" can cause mutations or changes in the DNA of cells, especially in the brain, where retrotransposon activity can increase with aging. This has led scientists to investigate whether there is a link between this activity and neurodegenerative diseases such as Alzheimer's.

In this study, researchers from the University of California San Diego, USA, examined the brains of people with and without Alzheimer's to better understand the activity of reverse transcriptase and L1 retrotransposons. They used advanced genetic analysis techniques, such as long-read sequencing and biochemical tests, to map the types of RNA generated by L1s in the brain.

What they found was surprising: They found almost no complete copies of L1, but instead hundreds of truncated or partial variants of these genetic elements. These variants could still produce active enzymes and had the potential to alter DNA, even though they were incomplete.

In addition, all of the brains analyzed showed some reverse transcriptase activity, although the Alzheimer’s brains had less activity, which may be related to the loss of neurons caused by the disease.

The figure shows how scientists measured reverse transcriptase (RT) activity in different parts of the brains of people with and without Alzheimer’s. Reverse transcriptase is normally associated with the HIV virus, but it can also be active in the brain and may be linked to diseases such as Alzheimer’s. A) The researchers took samples of brain tissue from people with Alzheimer’s (AD) and people without the disease (ND). They ground these samples to extract the proteins (this is called a “protein lysate”). They then mixed this material with a specific RNA molecule (from the MS2 virus, used as a control) and saw whether the reverse transcriptase in the samples could turn it into DNA (this is what this enzyme does). Finally, they used a laboratory test called qPCR to measure how many copies of DNA were produced, this shows the level of activity of the RT enzyme. B) The graph shows RT activity in people with Alzheimer's (AD, on the left) and people without the disease (ND, on the right), analyzing two regions of the brain: PFC (prefrontal cortex), an area linked to thought and memory. MTG (middle temporal gyrus), a region also important for language and memory. People without Alzheimer's (ND) generally had higher levels of RT activity than people with Alzheimer's. This may mean that the loss of neurons in people with Alzheimer's reduces this activity. C) Where in the brain RT is most active. Here, scientists compared two areas of the brain: Gray matter: where the bodies of neurons are (the most “active” part of the brain). White matter: where the “wires” (axons) that connect neurons run. RT activity was much higher in gray matter, which makes sense, since this is where neurons are, the cells most involved in this process. This discovery is important because it shows that even incomplete versions of L1 can influence brain function, both in healthy people and in those with diseases such as Alzheimer's.

This expands our understanding of how brain DNA can change over time, how this can affect brain health, and even how new therapies could be developed in the future to address these changes.

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Sequence diversity and encoded enzymatic differences of monocistronic L1 ORF2 mRNA variants in the aged normal and Alzheimer’s disease brain

Juliet Nicodemus, Christine S. Liu, Linnea Ransom, Valerie Tan, William Romanow, Natalia Jimenez, and Jerold Chun

Journal of Neuroscience, 14 May 2025, e2298242025 

https://doi.org/10.1523/JNEUROSCI.2298-24.2025

Abstract:

Reverse transcriptase (RT) activity in the human brain has been inferred through somatic retroinsertion/retrotransposition events, however actual endogenous enzymatic activities and sources remain unclear. L1 (LINE-1) retrotransposons bicistronically express ORF2, containing RT and endonuclease (EN) domains, and RNA binding protein ORF1, together enabling L1 retrotransposition and contributing to somatic genomic mosaicism (SGM). Here, we assessed endogenous RT activities and L1 mRNA diversity from cerebral cortical samples of 31 Alzheimer’s disease (AD) and non-diseased (ND) brains (both sexes) using enzymatic functional assays, targeted PacBio HiFi long-read sequencing, and quantitative spatial transcriptomics. Expected bicistronic, full-length L1 transcripts were absent from most samples, constituting <0.01% of L1 sequences, of which >80% were non-coding. Monocistronic ORF1 and ORF2 transcripts were identified across all samples, consistent with quantitative spatial transcriptomics that identified discordant ORF2 and ORF1 expression in neurons. All brains had RT activity, with AD samples showing less activity, consistent with neuronal loss of terminal AD vs. aged ND donors. Brain RT activity was higher in grey matter and correlated with increased neuronal ORF2 expression, further supporting neuronal contributions. Remarkably, >550 protein-encoding, polyA+ ORF2 sequence variants were identified, over 2x more than identified in the human reference genome (hg38). Experimental overexpression of full-length and truncated ORF2 variants revealed ∼50-fold RT and ∼1.3-fold EN activity ranges, supporting endogenous functional capacity of monocistronic ORF2 variants in the human brain. The vast sequence diversity of monocistronic ORF2 mRNAs could underlie functional differences in RT-mediated somatic gene recombination/retroinsertion and resulting genomic mosaicism in the normal and diseased brain.