Meyer K, Feldman HM, Lu T, Drake D, Lim ET, Ling KH, Bishop NA, Pan Y, Seo J, Lin YT, Su SC, Church GM, Tsai LH, Yankner BA. REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease. Cell Rep. 2019 Jan 29;26(5):1112-1127.e9. PubMed.

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  1. This new report from the Yankner lab provides convincing evidence that a dysregulation of neuronal gene transcription networks underlies events in brain that lead eventually to Alzheimer’s disease. Their work, looking not only at neurons derived from sporadic AD cases but also neurons genetically edited to be homozygous for the e4 allele of the major risk gene APOE, strongly points to the involvement of the transcription factor Repressor element 1-silencing transcription (REST). REST is known as a master negative regulator of neurogenesis and is also a key regulator of the aging brain’s stress response. Meyer at al., find that the nuclear translocation of REST and its ability to bind chromatin are disrupted in sporadic AD and APOE e4 neurons.

    In an earlier paper from the group (Lu et al., 2014), REST levels were shown to be reduced in the AD brain. Importantly, in individuals who exhibited AD pathology, nuclear REST was significantly elevated in cognitively preserved, as compared to cognitively impaired. This suggests that dysregulation of brain’s stress response in the presence of AD pathology causes cognitive decline rather than AD pathology alone. This has therapeutic relevance for AD and other aging-associated neurodegenerative diseases. This finding prompted us to investigate if REST protein could act as a readily accessible peripheral biomarker for AD. We have demonstrated evidence that REST may be reduced in AD and risk factors for AD (Ashton et al., 2017). 

    The question then is, why? Why is REST reduced in brain and why is it excluded from the nucleus where it performs its role as a repressive transcription factor? In the 2014 paper, REST levels are regulated by Wnt signaling and could be reduced by the Wnt antagonist Dickkopf-1 (Dkk1). The authors also showed that activating Wnt promoted the nuclear translocation of REST. This speaks to our work led by Dr. Richard Killick on the role of Dickkopf-1 in AD. It is plausible that the reduced levels of REST and its exclusion from the nucleus are the result of effects on Wnt signaling pathways through the ability of Aβ to induce Dkk1. Killick also described (October 2018 news) how Aβ synaptotoxicity drives further Aβ production via effects on Wnt signaling, again through the upregulation of Dkk1, which could be broken by the ROCK kinase inhibitor, fasudil. It would be interesting to now determine if fasudil might also reverse the effects on REST reported by the Yankner lab, i.e., its exclusion from the nucleus and downstream effects on gene transcription, and also its reduced levels in AD brain.

    View all comments by Richard Killick

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  1. In Alzheimer’s, Too Little REST Spurs Too Much Neurogenesis