New research finds that an HIV enzyme plays a crucial role in driving Alzheimer's-related brain pathology by altering the APP gene. The findings warrant "immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer's disease," say the authors of the study.
Alzheimer's also puts a significant strain on the American healthcare system. According to recent estimates, Alzheimer's and other forms of dementia cost the U.S. $226 billion in 2015, and loved ones spend billions of unpaid hours caring for people with the condition. About 40 percent of these caregivers develop depression.
The medical community is hard at work trying to understand how this debilitating disorder occurs and what can be done to stop it. For instance, one of the clues that researchers have so far is the so-called APP gene.
The APP gene encodes a protein called amyloid precursor protein found in the brain and spinal cord, among other tissues and organs.
While the exact role of the APP protein is still unknown, scientists have found links between mutations in this gene and the risk of early-onset Alzheimer's disease. Specifically, over 50 different mutations in the APP gene can trigger the condition, accounting for approximately 10 percent of all early-onset Alzheimer's cases.
New research, published in the journal Nature, offers unprecedented revelations into the APP gene. Scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA, found that the same type of enzyme that enables HIV to infect cells recombines the APP gene in a way that creates thousands of new genetic variants in the neurons of people with Alzheimer's.
The findings may not only explain how APP drives the toxic buildup of beta-amyloid proteins — which is a hallmark of Alzheimer's disease — but also "fundamentally change how we understand the brain and Alzheimer's disease," according to Dr. Jerold Chun, Ph.D., the senior author of the new paper.
Crucially, the new results suggest that antiretroviral therapies that are currently used to treat HIV may be useful for treating Alzheimer's too.
When gene recombination 'goes wrong'
Dr. Chun and his team used cutting-edge analysis techniques that focused on single- and multiple-cell samples to study the APP gene in Alzheimer's and healthy brain samples.
They found that the APP gene breeds new genetic variations within neurons through a process of genetic recombination. Specifically, the process requires reverse transcriptase, which is the same enzyme found in HIV.
Reverse transcription and "reinsertion of the genetic variants back into the original genome" created permanent DNA changes that occurred "mosaically."
"Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer's disease," explains Dr. Chun, who is also a professor and the senior vice president of Neuroscience Drug Discovery at SBP.
The researchers report that 100 percent of the brain samples that had the neurodegenerative condition also had a disproportionately high number of different APP genetic variations compared with healthy brains.
The study's senior author explains, "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," Dr. Chun adds. "The secret code is being used in healthy brains but also appears to be disrupted in Alzheimer's disease."
Treating Alzheimer's with HIV drugs
Dr. Chun and colleagues suggest that antiretroviral therapy that blocks the reverse transcriptase may be a successful treatment for Alzheimer's.
"Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer's disease."
Dr. Jerold Chun
"Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer's disease," the researcher adds.
The scientists also point out that seniors with HIV who take antiretroviral medication tend not to develop Alzheimer's disease, which may support the researchers' conclusions.
The scientists also say that their findings may serve to explain a mystery that has puzzled researchers for years. The medical community widely accepts the idea that the buildup of a toxic protein called beta-amyloid causes Alzheimer's neurodegeneration.
However, whenever researchers tested treatments that were designed to target this toxic buildup in clinical trials, such treatments failed.
But the new findings, say Dr. Chun and team, shed light on this baffling contradiction. "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 says.
"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."
Dr. Jerold Chun
Although the new findings are groundbreaking, much remains to be discovered, adds Dr. Chun. "Today's discovery is a step forward — but there is so much that we still don't know," he says.
"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."