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. 2019 Aug 20;9:12110. doi: 10.1038/s41598-019-47039-1

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Hypothetical model of AIE-induced adult pathology and the mechanisms of Donepezil reversal of AIE effects. AIE increases expression of adult hippocampal HMGB1 and RAGE consistent with increased signaling of this agonist-receptor combination. HMGB1-RAGE increases pNFκB transcription of RAGE feeding forward to enhance expression of DR3, which, in turn activates cell death caspase cascades as indicated by increased active caspase 3, the executioner caspase. RAGE is expressed on DCX + IR neuroprogenitors consistent with RAGE increasing DCX cell death that contributes to the persistent loss of neurogenesis after AIE. AIE increases RAGE, pNFkBp65 and increases H3K9me2, an epigenetic marker of gene silencing. Gene silencing involves histone methylation of H3K9me2 and is reciprocal with deacetylation, the loss of H3K9ac. HDAC2 is increased in neurons by NFkB consistent with reduced BDNF in response to RAGE-NFkB activation. Donepezil reversed RAGE, pNFkBp65, H3K9me2, DR3, caspase-3 and loss of DCX after AIE. These findings are consistent with an anti-inflammatory action of donepezil either through increasing acetylcholine and/or through anti-inflammatory microglial inhibitory mechanisms.