Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Kienlen‐Campard, Pascal; Smet, Charles De; Octave, Jean‐Noël

doi:10.1371/journal.pone.0099467

Cited by 59 publications

(43 citation statements)

References 55 publications

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“…In Tg2576 and APP751SL mice, characterized by overexpression of hAPP, hippocampal Egr1 was significantly decreased relative to WT controls after MWM training, in which mice were impaired on learning and memory phases. These data are in agreement with studies documenting epigenetic downregulation of Egr1 in neurons by APP (Hendrickx et al, 2013), a process that has shown to be mediated by CREB (Hendrickx et al, 2014), as overexpression of hAPP would be expected to further suppress Egr1 to a pathological degree. Studies thus far, however, have not investigated the relationship between amyloidogenic processes, Egr1 and tau pathology or how NF-κB alterations potentially link these changes in an AD model in which NFTs occur (e.g., 3xTg strain).…”

Section: Early Growth Response (Egr) Factorssupporting

confidence: 91%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

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Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

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Section: Early Growth Response (Egr) Factorssupporting

confidence: 91%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

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“…Also the decrease in acetylation level of histones at Egr1, c‐Fos and BDNF promoter is correlated with Alzheimer's disease (Hendrickx et al . ). Therefore, SIN3A silencing induced increase in H3K9/14 acetylation during amnesia might be a crucial factor for the recovery of memory loss through modulation of neuronal gene expression.…”

Section: Discussionmentioning

confidence: 97%

Transcriptional co‐repressor SIN3A silencing rescues decline in memory consolidation during scopolamine‐induced amnesia

Srivas

Thakur

2018

Journal of Neurochemistry

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Epigenetic modifications through methylation of DNA and acetylation of histones modulate neuronal gene expression and regulate long-term memory. Earlier we demonstrated that scopolamine-induced decrease in memory consolidation is correlated with enhanced expression of hippocampal DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in mice. DNMT1 and HDAC2 act together by recruiting a co-repressor complex and deacetylating the chromatin. The catalytic activity of HDACs is mainly dependent on its incorporation into multiprotein co-repressor complexes, among which SIN3A-HDAC2 co-repressor is widely studied to regulate synaptic plasticity. However, the involvement of co-repressor complex in regulating memory loss or amnesia is unexplored. This study examines the role of co-repressor SIN3A in scopolamine-induced amnesia through epigenetic changes in the hippocampus. Scopolamine treatment remarkably enhanced hippocampal SIN3A expression in mice. To prevent such increase in SIN3A expression, we used hippocampal infusion of SIN3A-siRNA and assessed the effect of SIN3A silencing on scopolamine-induced amnesia. Silencing of SIN3A in amnesic mice reduced the binding of HDAC2 at neuronal immediate early genes (IEGs) promoter, but did not change the expression of HDAC2. Furthermore, it increased acetylation of H3K9 and H3K14 at neuronal IEGs (Arc, Egr1, Homer1 and Narp) promoter, prevented scopolamine-induced down-regulation of IEGs and improved consolidation of memory during novel object recognition task. These findings together suggest that SIN3A has a critical role in regulation of synaptic plasticity and might act as a potential therapeutic target to rescue memory decline during amnesia and other neuropsychiatric pathologies.

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“…However, c-Fos and BDNF belong to the immediate early gene family and undergo very rapid epigenetic modifications 53,54 necessitating an early analysis of the histone acetylation status of their respective promotors (in particular at the CREB binding site), as we have done in this study. Despite the rapid (and in several models, transient) epigenetic changes in c-Fos and BDNF promotors, these modulations have long-lasting influence via the activator protein (AP)-1 complex and AP-1 binding region on promoters of numerous later response genes that participate in processes crucial for neuronal development and survival.…”

Section: Discussionmentioning

confidence: 99%

General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus

et al. 2016

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Background Early postnatal exposure to general anesthesia (GA) may be detrimental to brain development, resulting in long-term cognitive impairments. Older literature suggests that in utero exposure of rodents to GA causes cognitive impairments in the first-generation as well as in the second-generation offspring never exposed to GA. Thus, the authors hypothesize that transient exposure to GA during critical stages of synaptogenesis causes epigenetic changes in chromatin with deleterious effects on transcription of target genes crucial for proper synapse formation and cognitive development. They focus on the effects of GA on histone acetyltransferase activity of cAMP-responsive element-binding protein and the histone-3 acetylation status in the promoters of the target genes brain-derived neurotrophic factor and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (c-Fos) known to regulate the development of neuronal morphology and function. Methods Seven-day-old rat pups were exposed to a sedative dose of midazolam followed by combined nitrous oxide and isoflurane anesthesia for 6 h. Hippocampal neurons and organotypic hippocampal slices were cultured in vitro and exposed to GA for 24 h. Results GA caused epigenetic modulations manifested as histone-3 hypoacetylation (decrease of 25 to 30%, n = 7 to 9) and fragmentation of cAMP-responsive element-binding protein (two-fold increase, n = 6) with 25% decrease in its histone acetyltransferase activity, which resulted in down-regulated transcription of brain-derived neurotrophic factor (0.2- to 0.4-fold, n = 7 to 8) and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (about 0.2-fold, n = 10 to 12). Reversal of histone hypoacetylation with sodium butyrate blocked GA-induced morphological and functional impairments of neuronal development and synaptic communication. Conclusion Long-term impairments of neuronal development and synaptic communication could be caused by GA-induced epigenetic phenomena.

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Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

Cited by 59 publications

References 55 publications

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Transcriptional co‐repressor SIN3A silencing rescues decline in memory consolidation during scopolamine‐induced amnesia

General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus

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