Unexplored gene recombination in the brain linked to Alzheimer’s disease treatment

Unexplored gene recombination in the brain linked to Alzheimer's disease treatment
© iStock/kirstypargeter

New tech reveals DNA in neurons are ‘mixed and matched’, therefore the gene recombination could be a new form of Alzheimer’s disease treatment.

According to the Sanford Burnham Prebys Medical Discovery Institute (SBP), USA, scientists have identified the gene recombination in neurons that produces thousands of new gene variants within Alzheimer’s disease brains. The study uncovers, for the first time, how the Alzheimer’s-linked gene, APP, is recombined by using the same type of enzyme found in HIV – could this be a new wave of Alzheimer’s disease treatment?

Can gene recombination decipher a secret code?

Using new analytical methods specifically looking at single and multiple-cell samples, the researchers found that the APP gene, which produces the toxic beta amyloid proteins defining Alzheimer’s disease, 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 recombination, so the DNA sequence changes within the cell’s DNA blueprint.

Jerold Chun, M.D., Ph.D., senior author of the paper and professor and senior vice president of Neuroscience Drug Discovery at SBP says: “We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease. 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 Alzheimer’s disease 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 found 11 single-nucleotide changes identical to known mutations in ancestral Alzheimer’s disease – 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,” explains 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.”

Potential near-term Alzheimer’s disease treatment uncovered

Scientists found that the gene recombination process required an enzyme called reverse transcriptase, the same type of enzyme HIV uses to infect cells. Although there is no medical evidence that HIV or AIDS causes Alzheimer’s disease, existing FDA-approved antiretroviral therapies for HIV that block reverse transcriptase might also be able to halt the gene recombination process and could be explored as a new form of Alzheimer’s disease treatment.

An explanation for recent Alzheimer’s disease treatment setbacks

The amyloid hypothesis, or the theory that the accumulation of a protein called beta-amyloid in the brain causes Alzheimer’s disease, has driven Alzheimer’s research to date. However, treatments that target beta-amyloid have notoriously failed in clinical trials. However, the recent findings offer a potential answer to this mystery.

“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,” says Chun.

“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.”

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