Brain nerve cells of Alzheimer’s disease patients can produce thousands of variants of the APP gene, which codes for β-amyloid protein, a hallmark of the disease, researchers say. An enzyme important to the human immunodeficiency virus (HIV) is a key player in APP’s genetic diversity, supporting the potential for HIV antiretroviral therapies to treat Alzheimer’s.
“These findings may fundamentally change how we understand the brain and Alzheimer’s disease,” Jerold Chun, MD, PhD, professor and senior vice president of Neuroscience Drug Discovery at California’s Sanford Burnham Prebys Medical Discovery Institute (SBP) and the study’s lead author, said in a press release.
“Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer’s disease. Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer’s disease,” he said.
The study “Somatic APP gene recombination in Alzheimer’s disease and normal neurons” was published in Nature.
The diversity and complexity of the human brain are thought to be encoded within a constant genome — the complete set of genetic material present in a cell or organism. In 2015, however, a study showed that neurons from people with sporadic Alzheimer’s, the most common form of the disease, had a higher DNA content and more copies of the amyloid-β precursor protein (APP) gene when compared to neurons from people without the disease.
Neurons were shown to undergo genetic recombination (where their DNA is rearranged into new forms) and exhibited somatic variability, i.e., genomic mosaicisms where two or more populations of cells have different genomes. This is in contrast with what occurs in nature, where the genome is passed from cell to cell and expected to exist in the same way in every cell. However, the exact genomic changes underlying this mosaicism remained unknown.
Now, researchers have found that the APP gene can occur as thousands of different variants in the brains of people with sporadic Alzheimer’s disease when compared to healthy brains. The APP gene codes for the beta-amyloid protein that accumulates to form beta-amyloid plaques, one of the hallmarks of Alzheimer’s.
“Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer’s disease,” Chun said.
The team isolated DNA from the cell nucleus of neurons extracted from postmortem brain samples of six people with sporadic Alzheimer’s disease and six healthy controls.
Among all APP gene variants, researchers identified 11 that had a single change in their DNA sequence, absent in healthy neurons but identical to mutations seen in familial Alzheimer’s, a rare, inherited form of the disease.
“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,” Chun said.
The mechanism behind this genetic mosaicism, they found, involves a protein (enzyme) used by HIV to infect cells, called reverse transcriptase.
Although there is currently no evidence that HIV or AIDS increases the risk for Alzheimer’s disease, these findings suggest that FDA-approved antiretroviral therapies for HIV — which block the activity of reverse transcriptase — may halt the genetic recombination in Alzheimer’s disease.
The fact that Alzheimer’s disease occurs very rarely among HIV-positive people older than 65 strengthens the possible therapeutic benefits of the antiretroviral medications.
“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,” Chun said.
The diversity of APP gene variations that has now been disclosed also offers an explanation as to why therapies targeting beta-amyloid protein fail, especially those targeting a single form of the protein.
“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,” Chun said.
“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,” he said.
Researchers highlighted the importance of this discovery and how it opens further questions into the normal functioning of the brain and what goes awry in neurogenerative diseases such as Alzheimer’s. “Today’s discovery is a step forward — but there is so much that we still don’t know,” Chun said.
“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 said.
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