Scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) in San Diego, California, have identified gene recombination in neurons that produces thousands of new gene variants within Alzheimer's disease brains. The study, published online on November 21, 2018 in Nature, reveals for the first time how the Alzheimer's-linked gene, APP (the gene coding for amyloid precursor protein--see image), is recombined by using the same type of enzyme found in HIV. The article is titled “Somatic APP Gene Recombination in Alzheimer’s Disease and Normal Neurons.” 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, MD, PhD, , 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.
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