Somatic gene recombination of a gene that is central to Alzheimer disease (AD) occurs in the brain, according to a new study published in Nature. The finding could change our understanding of AD pathogenesis and suggests that existing HIV therapies could be useful in the treatment of AD.

Earlier in his career, Jerold Chun, senior author of the new study, demonstrated that part of the immunological recombinase is expressed in the brain. This finding initiated a search for a gene that undergoes recombination in the brain.

“Finding a gene that was recombined eluded everyone,” says Chun, “but many years of research finally pointed to a gene that could be recombined and was of central importance in familial AD and Down syndrome: APP, the gene that encodes amyloid precursor protein.”

Previous work demonstrated that copy number variations of APP were altered in sporadic AD (sAD), providing the first indication that the gene could undergo recombination. In the new study, Chun and colleagues analysed APP in detail.

The researchers first analysed APP RNA in small populations of neurons from people with sAD and healthy controls. They identified many previously unseen APP variants in neurons from patients with sAD that were rare in neurons from controls. The team then analysed whether neuronal DNA sequences were the source of variants. They used nine distinct approaches, all of which identified genomic complementary DNAs (gencDNAs) that corresponded to the RNA variants identified. The results confirmed the presence of APP variants in neuronal genomes and showed that the variation arises through genomic mosaicism.

Furthermore, in vitro experiments indicated that the formation of gencDNAs in cells depends on reverse transcriptase activity, presenting a novel potential therapeutic target. Interestingly, Chun and colleagues note that AD is rare among individuals aged >65 years who have received long-term therapy for HIV, which includes reverse transcriptase inhibitors. The combined observations suggest that currently used, FDA-approved HIV therapies, or modifications of these therapies, might be beneficial in the treatment of AD.

currently used, FDA-approved HIV therapies … might be beneficial in the treatment of AD

“Our findings suggest a new mechanism of neurodegeneration that involves altered or too much recombination producing toxic genes, RNAs and proteins,” explains Chun. “We will now work with clinical colleagues to test the hypothesis that appropriate reverse transcriptase therapies can treat AD.”