An indirect link between Alzheimer’s and HIV?
Scientists describe never-before-seen DNA recombination in the brain linked to Alzheimer's disease, related to the APP gene and an HIV-linked enzyme
LA JOLLA, Calif. & ORLANDO—In a study published in Nature, researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) report that they identified never-before-seen gene recombination in neurons that produces thousands of new gene variants within Alzheimer’s disease (AD) brains, revealing for the first time how the Alzheimer’s disease-linked gene known as APP is recombined by using the same type of enzyme found in HIV.
The scientists found that the gene recombination process required an enzyme called reverse transcriptase, the same type of enzyme HIV uses to infect cells. SBP stresses that there is no medical evidence that HIV or AIDS cause AD; however, existing FDA-approved antiretroviral therapies for HIV that block reverse transcriptase might, the institute says, “also be able to halt the recombination process and could be explored as a new treatment for Alzheimer’s disease. The scientists noted the relative absence of proven Alzheimer’s disease in aging HIV patients on antiretroviral medication, supporting this possibility.”
“Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer’s disease,” said Dr. Jerold Chun, senior author of the paper and the senior vice president of Neuroscience Drug Discovery at SBP, as well as a professor there. “Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer’s disease.”
Added first author Dr. Ming-Hsiang Lee, a research associate in the Chun laboratory: “Reverse transcriptase is an error-prone enzyme, meaning it makes lots of mistakes. This helps explain why copies of the APP gene are not accurate in Alzheimer’s disease and how the diversity of DNA in the neurons is created.”
To conduct the research, the scientists at SBP used new analytical methods focused on single- and multiple-cell samples, and they found that the APP gene, which produces the toxic beta amyloid proteins defining AD, gives rise to novel gene variants in neurons, creating a genomic mosaic. The process required reverse transcription and reinsertion of the variants back into the original genome, producing permanent DNA sequence changes within the cell’s DNA blueprint.
“We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease,” explained Chun. “Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer’s disease.”
One hundred percent of the AD brain samples contained an over-abundance of distinct APP gene variants, compared to samples from normal brains. Among these Alzheimer’s-enriched variations, the scientists identified 11 single-nucleotide changes identical to known mutations in familial AD, a very rare inherited form of the disorder. Although found in a mosaic pattern, the identical APP variants were observed in the most common form of Alzheimer’s disease, further linking gene recombination in neurons to disease.
“These findings may fundamentally change how we understand the brain and Alzheimer’s disease,” noted Chun. “If we imagine DNA as a language that each cell uses to ‘speak,’ we found that in neurons, just a single word may produce many thousands of new, previously unrecognized words. This is a bit like a secret code embedded within our normal language that is decoded by gene recombination. The secret code is being used in healthy brains but also appears to be disrupted in Alzheimer’s disease.”
And if the research findings are applicable to actual curative results in AD patients, the benefits could be reaped very soon.
“There is currently no way to prevent, treat or cure AD. The healthcare and societal impacts of AD are increasing as the U.S. population ages. An effective treatment is urgently needed. This study identifies an underlying cause of the disease, and points to a near-term treatment for AD,” Chun said. “On average, it takes 10 years for a drug to receive FDA approval. This study provides scientific rationale for testing existing FDA-approved antiretroviral drugs for HIV to evaluate effectiveness in AD patients. Studies could begin right away, because these drugs have already undergone extensive safety testing and have been used safely for years to treat HIV.”
The findings could also go a long way toward explaining why clinical trials in experimental AD drugs have been such a disappointment so far. As SBP notes, the amyloid hypothesis—the theory that accumulation of a protein called beta-amyloid in the brain causes AD—has driven most of the Alzheimer’s research to date. However, treatments that target beta-amyloid have, as SBP put it, “notoriously failed in clinical trials.”
“The failures of AD clinical trials may reflect that there are many more forms of toxic variants of APP (amyloid precursor protein) than previously thought,” Chun remarked. “APP is a gene known to be associated with AD—and these APP variants were most likely missed by drugs targeting the single form of APP.
“The thousands of APP gene variations in Alzheimer’s disease provide a possible explanation for the failures of more than 400 clinical trials targeting single forms of beta-amyloid or involved enzymes. APP gene recombination in Alzheimer’s disease may be producing many other genotoxic changes as well as disease-related proteins that were therapeutically missed in prior clinical trials. The functions of APP and beta-amyloid that are central to the amyloid hypothesis can now be re-evaluated in light of our gene recombination discovery.”
Chun says that his team’s discovery is a step forward, but “there is so much that we still don’t know,” he acknowledges. “We hope to evaluate gene recombination in more brains, in different parts of the brain and involving other recombined genes—in Alzheimer’s disease as well as other neurodegenerative and neurological diseases—and use this knowledge to design effective therapies targeting gene recombination.”