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

November 21, 2018, Sanford Burnham Prebys Medical Discovery Institute
Credit: CC0 Public Domain

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 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 —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.

Explore further: Diabetes medications may reduce Alzheimer's disease severity

More information: Ming-Hsiang Lee et al, Somatic APP gene recombination in Alzheimer's disease and normal neurons, Nature (2018). DOI: 10.1038/s41586-018-0718-6

Related Stories

Diabetes medications may reduce Alzheimer's disease severity

November 1, 2018
People with Alzheimer's disease who were treated with diabetes drugs showed considerably fewer markers of the disease—including abnormal microvasculature and disregulated gene expressions—in their brains compared to Alzheimer's ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Researchers discover possible cause for Alzheimer's and traumatic brain injury

September 26, 2018
Rutgers researchers have discovered a new mechanism that may contribute to Alzheimer's disease and traumatic brain injury. They now hope to launch a clinical trial to test the treatment in humans.

Mutation discovered to protect against Alzheimer's disease in mice

May 16, 2018
Researchers at the RIKEN Center for Brain Science have discovered a mutation that can protect against Alzheimer's disease in mice. Published in the scientific journal Nature Communications, the study found that a specific ...

Gene variant protecting against Alzheimer's disease decreases plasma beta-amyloid levels

June 20, 2017
New research from the University of Eastern Finland shows that the APP gene variant protecting against Alzheimer's disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a very significant ...

The onset of Alzheimer's disease: The importance of family history

February 26, 2018
You're about to turn 60, and you're fretting. Your mother has had Alzheimer's disease since the age of 65. At what age will the disease strike you? A Canadian study published in JAMA Neurology shows that the closer a person ...

Recommended for you

Does diabetes damage brain health?

December 14, 2018
(HealthDay)—Diabetes has been tied to a number of complications such as kidney disease, but new research has found that older people with type 2 diabetes can also have more difficulties with thinking and memory.

Amyloid pathology transmission in lab mice and historic medical treatments

December 13, 2018
A UCL-led study has confirmed that some vials of a hormone used in discontinued medical treatments contained seeds of a protein implicated in Alzheimer's disease, and are able to seed amyloid pathology in mice.

Study links slowed brainwaves to early signs of dementia

December 13, 2018
To turn back the clock on Alzheimer's disease, many researchers are seeking ways to effectively diagnose the neurodegenerative disorder earlier.

New discoveries predict ability to forecast dementia from single molecule

December 11, 2018
Scientists who recently identified the molecular start of Alzheimer's disease have used that finding to determine that it should be possible to forecast which type of dementia will develop over time—a form of personalized ...

Researchers classify Alzheimer's patients in six subgroups

December 5, 2018
Researchers studying Alzheimer's disease have created an approach to classify patients with Alzheimer's disease, a finding that may open the door for personalized treatments.

Neuroscientists pinpoint genes tied to dementia

December 3, 2018
A UCLA-led research team has identified genetic processes involved in the neurodegeneration that occurs in dementia—an important step on the path toward developing therapies that could slow or halt the course of the disease. ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Robin_Whittle
not rated yet Nov 21, 2018
Reverse transcriptase driving genetic change is part of normal brain function?? This would be an even more profound finding than its role in AD.

The article is behind a paywall, but there is a writeup at https://www.genom...-neurons and a detailed commentary which seems to cover all the interesting details: https://www.natur...-07334-9 .

Robin_Whittle
not rated yet Nov 21, 2018
I had thought that reverse transcriptase (RT) was only found in retrovirus-infected cells. However there is a eukarotic RT with a specific (according to current understanding) purpose of extending telomeres: https://en.wikipe...criptase As best I understand it, this normally only works with a short attached RNA sequence as its template.

There's no mention of this recent research identifying the source of the RT in the changes they observed. Anti-retroviral therapies for HIV must be effective at reducing retroviral RT activity. If they inhibited telomerase RT then I would have thought that this would have serious consequences for reproduction, while also reducing cancer. On this, admittedly highly speculative and poorly informed basis, the ability of anti-retroviral HIV treatments to reduce the incidence of AD indicates that retroviral RT is involved in AD. If so, then where does it come from??

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.