Alzheimer’s disease is the most common cause of dementia, affecting over 25 million people worldwide and costing more than US$400 billion a year (1). The number of Alzheimer’s patients is predicted to rise to over 60 million by 2050. Alzheimer’s disease causes irreversible loss of memory and cognitive abilities. There is currently no cure or effective treatment options for Alzheimer’s patients.
Part of the reason that we don’t have an effective treatment for Alzheimer’s disease is because we don’t know the exact cause. However, we do know that abnormal proteins accumulate in the brains of Alzheimer’s patients. These proteins aggregate inside neurons, becoming toxic amyloid plaques and tangled tau fibres. This causes neurons to die and areas of the brain to shrink.
Genetic Causes of Alzheimer’s Disease
Genetic mutations in the Amyloid Precursor Protein (APP) gene are linked to early-onset Alzheimer’s disease. The theory is that mutant APP proteins are not processed properly into normal amyloid and instead form toxic amyloid-β proteins that become plaques.
A surprising new study from scientists at the Sanford Burnham Prebys Medical Research Institute (SBP) in San Diego, California, shows that some of the Alzheimer’s-causing mutations in the APP gene may come from genetic recombination inside neurons (2).
Genetic Recombination May Contribute to Alzheimer’s Disease
Genetic recombination occurs most commonly in germ cells where chromosomes swap whole sections of DNA. This process increases genetic diversity in offspring. Scientists hypothesize that genetic recombination may also occur in brain cells because previous studies have found that brain cells from the same person can have very different DNA.
A recent study by SBP scientists looked for recombination in the Alzheimer’s-causing APP gene inside human neurons. They found thousands of different variations in the APP gene and corresponding messenger RNA. These variations included 11 mutations associated with early-onset Alzheimer’s disease, as well as 12 novel variations that have not been previously reported. The scientists introduced APP RNA variants into cultured cells and these variants caused cell death. Therefore, these variants could potentially contribute to disease in humans.
The 11 disease-causing mutations only occurred in neurons from Alzheimer’s patients, not in brain cells from healthy controls. However, other variations in the APP gene did occur in neurons from healthy control brains as well as from Alzheimer’s patients. Although this 3 to 5 times more common in neurons from Alzheimer’s patients.
Furthermore, all APP genetic changes only occurred inside neurons. The scientists found no changes in the APP gene in non-neuronal brain cells or in cultured kidney or lung cells. They also found no changes in another gene associated with Alzheimer’s, called PSEN1.
Antiviral Medications Can Block Genetic Recombination
The researchers found the same genetic variations in the DNA of the APP gene and in corresponding messenger RNA, using a combination of sequencing and DNA in-situ hibridization (DISH). Therefore, they propose that these genetic variations can be transcribed and could contribute to toxic amyloid plaques in Alzheimer’s disease patients. However, the genetic variations also occur in normal, healthy brain tissue. Therefore, more research is needed to understand why this happens and what it means.
To work out what causes this genetic variation in the APP gene in neurons, the scientists introduced mutant human APP into cultured hamster ovary (CHO) cells. The cells produced copies of the mutant DNA only if scientists caused DNA strand breaks with H2O2. Scientists could block mutant DNA formation if they used antiviral medication commonly used to treat HIV patients. These drugs worked by blocking reverse transcriptase activity inside the CHO cells.
From this data, the scientists suggest that some of the disease-causing genetic variation in neurons might be caused by mutant RNA being reverse transcribed or ‘retro-inserted’ into cell’s DNA. Much like how viruses, such as HIV, insert into host DNA and replicate inside host cells. This process can be blocked by stopping DNA breaks or by blocking reverse transcriptase enzymes.
Further support for this idea comes from the fact that HIV patients taking reverse transcriptase-blocking medications rarely develop Alzheimer’s disease (2).
“Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer’s disease,” said Jerold Chun, M.D., Ph.D, lead author of the paper, in a press release. “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.”
Conclusions
This study shows that recombination occurs in the APP gene in healthy neurons and in neurons from Alzheimer’s patients. This recombination gives rise to thousands of different APP gene variants that are present in both healthy and diseased neurons, but not in non-neuronal cells. Recombination doesn’t seem to occur in another Alzheimer’s gene, PSEN1.
Recombination relies on reverse transcriptase enzymes to insert genetic material into the genome. These enzymes are blocked by medications commonly used to treat HIV patients. Therefore, the authors of this study suggest that these drugs could help prevent Alzheimer’s disease, or stop Alzheimer’s patients from getting worse. Clinical studies are needed to test this hypothesis.
Biobanks support this kind of high impact research by providing access to high quality patient samples and data.
References
World Health Organisation Dementia Fact Sheet. (Online) Accessed 28 December, 2018.
Lee et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 2018.
