Palomer, E;
Martín-Segura, A;
Baliyan, S;
Ahmed, T;
Balschun, D;
Venero, C;
Martin, MG;
(2016)
Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons.
Cell Rep
, 16
(11)
pp. 2889-2900.
10.1016/j.celrep.2016.08.028.
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Abstract
Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.
| Type: | Article |
|---|---|
| Title: | Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.celrep.2016.08.028 |
| Publisher version: | https://doi.org/10.1016/j.celrep.2016.08.028 |
| Language: | English |
| Additional information: | © 2016 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Acetylation, Aging, Animals, Brain-Derived Neurotrophic Factor, Cholesterol, Chromatin, Cognition, Epigenesis, Genetic, Hippocampus, Histones, Long-Term Potentiation, Lysine, Methylation, Mice, Inbred C57BL, N-Methylaspartate, Neurons, Promoter Regions, Genetic, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Transcription, Genetic, Voriconazole |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10051150 |
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