It’s thought that the sequence of the genome remains the same throughout the life of an organism. But scientists have discovered a kind of genetic recombination, in which the sequence of a gene changes, in brains affected by Alzheimer’s disease. Those changes were happening in a gene called APP that has been linked to Alzheimer’s in previous work; the APP gene can generate aberrant beta-amyloid proteins that are characteristic of the disease. In this work, researchers found many different variations of the APP gene in neurons. The findings have been published in Nature, and are described in the videos.
“We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease," noted the senior author of the report Jerold Chun, M.D., Ph.D., the senior author of the paper, professor and senior vice president of Neuroscience Drug Discovery at SBP. "Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer's disease."
Every sample the researchers analyzed carried high levels of different APP variants compared to healthy brains. Many cycles had happened in which the APP gene underwent reverse transcription, and after changes were made, the newly-made APP gene variant was reinserted back into the genome. The researchers found some variants that were identical to those found in a rare form of inherited Alzheimer’s disease.
"These findings may fundamentally change how we understand the brain and Alzheimer's disease," said 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."
An enzyme called reverse transcriptase is critical to the recombination process, and that enzyme is also crucial to a mechanism used by HIV. Therefore, it's possible that some HIV therapeutics that target reverse transcriptase may be useful in treating Alzheimer’s. The scientists noted that Alzheimer’s is rarely observed in aged HIV patients, suggesting this idea should be pursued.
"Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer's disease," noted Chun. "Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer's disease."
"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,” said first author Ming-Hsiang Lee, Ph.D., a research associate in the Chun laboratory.
While beta-amyloid plaques are thought to be linked to the development of Alzheimer’s disease, therapeutics aimed at these plaques have not been successful. With Alzheimer’s projected to impact 14 million people by 2060, it’s important to create therapies to treat this devastating disease.
"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," noted 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."
"Today's discovery is a step forward, but there is so much that we still don't know," said Chun. "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.
"It is important to note that none of this work would have been possible without the altruistic generosity of brain donors and their loving families, to whom we are most grateful. Their generosity is yielding fundamental insights into the brain, and are leading us toward developing new and effective ways of treating Alzheimer's disease and possibly other brain disorders, potentially helping millions of people. There is much more important work to be done,” he concluded.