Never-before-seen DNA recombination in the brain linked to Alzheimer’s disease

3D illustration of Interconnected neurons with electrical pulses

Scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified gene recombination in neurons that produces thousands of new gene variants within Alzheimer’s disease brains. The study, published today in Nature, reveals for the first time how the Alzheimer’s-linked gene, APP, is recombined by using the same type of enzyme found in HIV. 

Using new analytical methods focused on 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 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,” says Jerold Chun, M.D., Ph.D., senior author of the paper and 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.”

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 identified 11 single-nucleotide changes identical to known mutations in familial 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,” says 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 treatment uncovered  

The 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 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,” says Chun. “Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer’s disease.”

 

Adds first author Ming-Hsiang Lee, Ph.D., 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.”

An explanation for recent clinical trial setbacks

The amyloid hypothesis, or the theory that 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. Today’s 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.”   

Close of one chapter opens another 

“Today’s discovery is a step forward—but there is so much that we still don’t know,” says 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.”

He adds, “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.”

 

About Alzheimer’s disease

Alzheimer’s disease is a public health crisis. The cause of the disease remains unknown—and no meaningful treatment exists. Nearly six million people in the U.S. are living with Alzheimer’s disease, a number projected to reach 14 million by 2060 as the population ages. The annual health care system costs to care for people with the disease exceeds a quarter of a trillion dollars, according to the Alzheimer’s Association. The disease also places high burdens on family members: Caregivers of individuals with dementia report substantial emotional, financial and physical difficulties. 

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Q&A with Jerold Chun

Jerold Chun, M.D., Ph.D., professor and senior vice president of Neuroscience Drug Discovery at SBP, answered a few questions about the Nature study he authored, titled “Somatic APP gene recombination in Alzheimer’s disease and normal neurons.

If you are a reporter and have additional questions about the study, please contact Susan Gammon, Ph.D., at sgammon@sbpdiscovery.org.
 

  • What are the key takeaways from this discovery?

    There are three main takeaways from this discovery.
    1. The findings help scientists understand how the brain works normally and what goes wrong in AD—a fundamental discovery that reveals a near-term treatment for the disease.
    2. The discovery describes why existing medicines—currently FDA approved to treat HIV—offer a potential treatment option for Alzheimer’s disease (AD).
    3. It also provides a possible explanation for why previous clinical trials for AD—more than 300 in the last decade—have failed.
  • Why is this study important?
    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.
  • How does this finding offer hope to patients? What will your discovery mean to people with Alzheimer’s disease (AD)?
    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.
  • Why were you able to make the discovery now?
    Our study used new technology that allowed us to examine neurons one at a time—individually and in small sets. This enabled us to show, for the first time, that genes are “mixed and matched” or recombined in the brain, creating thousands of potentially toxic combinations that have never been seen before.
  • Does your discovery explain why AD drugs have failed in clinical trials?
    Yes. 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. 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.
  • Was there foundational research that led to this breakthrough?
    This new discovery stems from my lab’s previous research showing how single brain cells (neurons) can have different genomes—an aspect called “genomic mosaicism.”
    This research showed how Alzheimer’s patients have brains with altered mosaicism through more copies and fragments of the APP gene.

    This study identifies a diverse universe of never-before-seen APP gene variations and provides an explanation for how these gene variations are created in AD.
  • How is this research any different from other studies that claim breakthrough status?
    This is the first report of neuronal gene recombination in the brain—a biological process that “mixes and matches” gene pieces, creating new gene variations (variants) that are then re-inserted back into our DNA—changing our genetic blueprint.

    In individuals with AD, neuronal recombination creates a myriad of APP gene variants, many of which are not observed in normal brains and may be pathological. Creating gene variants requires an enzyme called reverse transcriptase, the same type of enzyme used by HIV to infect cells. There are a number of clinically safe, FDA-approved medicines used to treat HIV that block reverse transcriptase. These medicines can now be explored as a possible way to block the creation of pathological APP gene variants to treat AD in the very near future.
  • How many brain samples did you study?
    A total of 13 brain samples were studied: seven from individuals with Alzheimer’s disease, and six without.
  • Do you think the reverse transcriptase used in HIV is the same used in our brains?
    No. It is virtually certain that they are different; however, they both carry out the same enzymatic function.
  • Does this research provide any insight into the tau tangles associated with Alzheimer’s disease?
    We did not study this issue but are currently pursuing it.
  • Is DNA recombination seen in other parts of the body?
    Cells of our immune system recombine DNA (called “VDJ recombination”)—which creates the diversity that allows the immune system to recognize a universe of unwanted intruders. Our sex cells, or gametes, also recombine DNA in a different way (called “homologous recombination”)—which creates the uniqueness of us. Our study shows for the first time that DNA recombination occurs in the brain.
  • Do these findings potentially impact additional diseases?
    Yes. In rare cases, neurodegenerative or neurological diseases such as autism, Parkinson’s disease, depression and schizophrenia are linked to gene mutations or amplifications—but the most common forms of these diseases seem to lack these links. Today’s findings support the possibility that gene recombination may underlie the most common forms of one or more of these disorders.
  • Are there additional takeaways from the study?
    This study also provides an explanation for how the brain may normally store long-term memories, how it learns and how it changes (called “plasticity”), which is consistent with AD’s effects on memory. DNA, one of the most stable biological molecules in nature that can store information, could be used to retain long-term memories. Neuronal gene recombination could thus be a way to “record” as well as “play back” information, having normally beneficial but also pathologically detrimental effects.
  • How long did it take to achieve this research breakthrough?
    This is a culmination of more than 25 years of work.
  • Is any part of this research patented?
    SBP has filed two patent applications on the subject matter of the publication. Details are contained in the Nature paper under “Competing interests.”
  • Have any discussions with pharma or biotech companies about this research taken place?
    We are considering a number of options including biopharma partnerships, investments and spin-out opportunities and will develop our business strategy after we evaluate those options. SBP is committed to pursuing a business model that will advance this discovery toward patient benefit.
  • What steps are needed to turn this finding into real action for patients? What are the hurdles involved in getting this discovery to people with Alzheimer’s disease?
    Controlled clinical trials should be undertaken to establish the agents and dosing for optimal efficacy and safety of antiretroviral drugs to prevent and/or treat AD. Please consult your physician to evaluate the pros and cons of any medical treatment.
  • Where could someone go to donate her or his brain to research?
    There are a number of worthy organizations that accept brain donations. The National Institutes of Health NeuroBioBank (neurobiobank.nih.gov/donors-how-become-donor) and your preferred university body donation programs (e.g., www.ucop.edu/ad-program) can assist you in the process. Your local chapter of the Alzheimer’s Association may also direct you to appropriate resources.