Alternative splicing in aging and Alzheimer's disease: Highlighting the role of tau and estrogen receptor α isoforms in the hypothalamus.

Human genes show the highest efficacy of alternative splicing (AS) in the brain as compared to other tissues. Within the brain, a remarkably rich diversity of AS events was identified in the hypothalamus. The AS frequency is increased in the aging brain. Such AS events, as intron retention and accumulation of circular RNAs, were acknowledged as some of the main hallmarks of the aging brain. In Alzheimer's disease (AD) pivotal (tau gene, in particular), risk, candidate and other genes show significant alterations in AS. Therefore AD has been suggested to be a disease of dysregulated AS. One of the reported risk factors for AD is estrogen deficiency that may interfere with the extension of neurobrillary tangles. Mounting evidence suggests that estrogens may decrease hyperphosphorylated tau deposition in the brain. Furthermore, AS of estrogen receptor α (ERα) mRNA is decreased in AD brain areas with the highest tau load. These potential interactions among tau, estrogens, and ERα AS may be important for the development of therapeutic and preventive strategies for AD. The intriguing point is that the amount of splice variants of ERα in the hypothalamus and the hippocampus is increased in aging and decreased in AD, while ERα is one of the regulators of AS and is subject to AS itself.