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Alzheimer's Disease Gene Undergoes Somatic Recombination in Neurons

NEW YORK (GenomeWeb) – Researchers have uncovered somatic recombination events in the APP gene in both people with and without Alzheimer's disease, some of which might give rise to variants that contribute to the disease.

The process appears to rely on reverse transcriptase, suggesting HIV antiretroviral drugs that block this enzyme as a potential new treatment for Alzheimer's.

The APP gene encodes the amyloid-β precursor protein, which, under the amyloid hypothesis, is thought to cause Alzheimer's disease when it is cleaved and forms toxic amyloid-β peptides.

Researchers from the Sanford Burnham Prebys Medical Discovery Institute sought to uncover whether APP genetic mosaicism was present in people with Alzheimer's. Mosaicism, in which genetic mutations arise in a subset of cells, is common in the brain and has been linked to neurological diseases like Alzheimer's, they noted. In addition, people with the sporadic form of Alzheimer's have been found to harbor more copies of the APP gene within their neurons than individuals without the condition.

As they reported today in Nature, the researchers uncovered numerous APP recombination events within patients' neurons, including ones resulting in mutations that have been linked to the familial form of the disease.

"We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease," senior author Jerold Chun, a researcher at Sanford Burnham, said in a statement. "Gene recombination was discovered as both a normal process for the brain and one that goes wrong in Alzheimer's disease."

Using RT-PCR, they identified a suite of APP variants in mRNA isolated from neuronal nuclei obtained from the prefrontal cortex of people with and without sporadic Alzheimer's disease. While some of the variants were expected splice variants, others were of unexpected size and often resulted in missing central exons or intra-exonic junctions linking distal exons.

The researchers found the same variants when they analyzed genomic DNA isolated from neurons, suggesting that these alterations were embedded in the neurons' genomes.

Chun and his colleagues were also able to detect these embedded APP variants — which they dubbed genome complementary DNAs (gencDNAs) — through two independent approaches: a DNA in situ hybridization method based on ACD's BaseScope assay and a custom Agilent SureSelect targeted DNA pulldown assay.

Alzheimer's patients, though, harbored gencDNAs that were distinct from those of controls, the researchers reported. Using long reads generated by Pacific Biosciences' circular consensus sequencing method, they identified 6,299 unique sequences from the neuronal nuclei of Alzheimer's patients and 1,084 unique sequences in nuclei from controls. In addition, gencDNAs from control brains largely included the canonical splice variants, while those from diseased brains had lower levels of one canonical splice variants and none of the other.

Neurons from individuals with sporadic Alzheimer's also harbored 11 mutations linked to the familial form of the disease.

Further, the researchers uncovered APP gencDNAs in the neurons of a mouse model of Alzheimer's disease, though not in other cell types or in control mice. They added that gencDNA variants appeared to accumulate as the mice aged.

When they expressed one of the canonical splice variants in a cell line with endogenous reverse transcriptase, the researchers initially found no gencDNAs. But when they induced DNA strand breaks, they noted novel gencDNAs. Endogenous reverse transcriptase activity, they added, was needed to produce gencDNAs as well as variant RNAs.

This suggested to the researchers that blocking reverse transcriptase activity could be a potential Alzheimer's treatment. "Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer's disease," Chun said.

In a related commentary appearing in Nature, Guoliang Chai and Joseph Gleeson from the University of California, San Diego noted that more research is needed to learn about how the gencDNAs become mutated from the initial APP sequence and whether their accumulation is a cause or a byproduct of Alzheimer's disease.

They were also cautious about the potential use of antiretrovirals, saying it would be "interesting to test whether inhibitors of reverse transcriptase can prevent the accumulation of gencDNAs."