Hot Topic: Somatic APP gene recombination in normal and Alzheimer’s disease neurons

A new facet of the human brain has been reported [1] involving a first example of somatic gene recombination in neurons, representing a normal neural mechanism whose disruption could underlie the most common (sporadic) forms of Alzheimer’s disease. Mosaic and somatic recombination of Amyloid Precursor Protein (APP) was identified in this well-known Alzheimer’s disease gene, where increased copies and mutations in rare families or Down syndrome are considered causal. Recombination generates thousands of previously unknown gene variants characterized as “genomic complementary DNAs” or “gencDNAs” that could show identical sequences to cDNAs copied from brain-specific spliced RNAs, as well as myriad truncated forms characterized by exonic deletions and “intraexonic junctions” to produce novel sequences that become “retro-inserted” into the genome of single neurons, with neurons showing from 0 to 13 copies. Recombination appeared to require gene transcription, reverse transcriptase activity and DNA strand breaks. Both forms and numbers of APP gencDNAs were altered and increased in sporadic Alzheimer’s disease. Recombination might normally provide a way to alter post-mitotic neuronal genomes to “record” preferred gene variants for later “playback” without a need for gene splicing, towards optimizing or fine-tuning gene expression, representing a form of memory. The involvement of reverse transcriptase activities implicate potential Alzheimer’s disease therapeutics using reverse transcriptase inhibitors, a possibility supported epidemiologically by relatively rare cases of Alzheimer’s disease in aged HIV patients. Recombination could generate new therapeutic targets. Other recombined genes and affected diseases are possible.

Comments by Jerold Chun, Sanford Burnham Prebys Medical Discovery Institute

(1) Lee MH et al. (2018). Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature, doi: 10.1038/s41586-018-0718-6. [Epub ahead of print]. [PMID:30464338].

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