Co-housing reverses memory decline by epigenetic regulation of brain-derived neurotrophic factor expression in an animal model of Alzheimer’s disease

Hsiao, Ya Hsin; Hung, Hui Chi; Yu, Yang; Su, Chun Li; Chen, Shun Hua; Gean, Po Wu

doi:10.1016/j.nlm.2017.02.020

Cited by 15 publications

(9 citation statements)

References 35 publications

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“…For instance, aging reduced basal levels, while fear conditioning increased expression of total Bdnf mRNA and exon IV specific transcripts (Chapman et al, 2012). In animal models of AD, occupancy of HDAC2 in the promoter region of Bdnf exon IV contribute to the reduction of BDNF in APP/PS1 mice (Hsiao et al, 2017) and infusion of amyloid fibrils into the hippocampus of rats induces HDAC2 occupancy at promoter VI of Bdnf and thus decreases Bdnf expression (Hendrickx et al, 2014). In our study, increased cytosine methylations were observed in the promoter region of Bdnf exon I, III, IV, and VI, which may contribute to the long lasting hippocampal BDNF reduction induced by general anesthesia.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

Qian

Geng

et al. 2020

Front. Aging Neurosci.

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DNA methylation is an essential epigenetic mechanism involving in gene transcription modulation. An age-related increase in promoter methylation has been observed for neuronal activity and memory genes, and participates in neurological disorders. However, the position and precise mechanism of DNA methylation for memory gene modulation in anesthesia related cognitive impairment remained to be determined. Here, we studied the effects of sevoflurane anesthesia on the transcription of memory genes in the aged rat hippocampus. Then, we investigated changes in DNA methylation of involved genes and verified whether dysregulated DNA methylation would contribute to anesthesia induced cognitive impairment. The results indicated that sevoflurane anesthesia down-regulated the mRNA and protein levels of three memory genes, Arc, Bdnf, and Reln, which were accompanied with promoter hypermethylation and increased Dnmt1, Dnmt3a, and Mecp2 expression, and finally impaired hippocampus dependent memory. Furthermore, inhibition of DNA hypermethylation by 5-Aza rescued sevoflurane induced memory gene expression decrease and cognitive impairment. These findings provide an epigenetic understanding for the pathophysiology of cognitive impairment induced by general anesthesia in aged brain.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

Qian

Geng

et al. 2020

Front. Aging Neurosci.

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“…To further understand the role of HDACs in pain, changes in HDAC2 recruitment to the promoter of GAD65 and KCC2 and the effect of HDAC2 knockdown on electrophysiological function of inhibitory interneurons in the spinal cord needs to be confirmed. Other possible downstream targets of HDAC2 in pain processing, such as MOR, BDNF, and mGlu2 receptor could also be evaluated (Kurita et al, 2012; Hsiao et al, 2017; Liao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression

et al. 2019

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Neuropathic pain is a worldwide health concern with poor treatment outcomes. Accumulating evidence suggests that histone hypoacetylation is involved in development and maintenance of neuropathic pain. Thus, many natural and synthetic histone deacetylase (HDACs) inhibitors were tested and exhibited a remarkable analgesic effect against neuropathic pain in animals. However, studies evaluating specific subtypes of HDACs contributing to neuropathic pain are limited. In this study, using the chronic constriction injury (CCI) rat model, we found that mRNA and protein levels of HDAC2 were increased in the lumbar spinal cord of rats after sciatic nerve injury. Intrathecal injection of TSA, a pan-HDAC inhibitor, suppressed the increase in HDAC2 protein but not mRNA, and showed a dose-dependent pain-relieving effect. By introducing HDAC2-specific shRNA into the spinal cord via a lentivirus vector, we confirmed that HDAC2 mediates mechanical and thermal hyperalgesia after nerve injury. Further examination found two essential participants in neuropathic pain in the inhibitory circuit of the central nervous system: GAD65 and KCC2 were increased in the spinal cord of CCI rats after HDAC2 knockdown. Thus, our research confirmed that HDAC2 was involved in mechanical and thermal hyperalgesia induced by peripheral nerve injury. Furthermore, GAD65 and KCC2 were the possible downstream targets of HDAC2 in pain modulation pathways.

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“…Recently it was found that in APP/PS1dE9 mice SUMOylation by SUMO1 of HDAC1, which can be induced by Aβ exposure, reduced cognitive impairments and neuropathology, and may thus serve as a defense mechanism against Aβ toxicity (Tao et al, 2017). Another study in the APP/PS1dE9 mice implicated histone deacetylation of Bdnf by HDAC2 in memory performance (Hsiao et al, 2017), and others revealed that treatment with HDAC inhibitors can ameliorate cognitive impairments in these mice (Kilgore et al, 2010). No global differences in hippocampal histone (H) 3 and H4 acetylation levels were detected.…”

Section: Discussionmentioning

confidence: 99%

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease

Lardenoije

Hove

Havermans

et al. 2018

Molecular and Cellular Neuroscience

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Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age-related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes.

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Co-housing reverses memory decline by epigenetic regulation of brain-derived neurotrophic factor expression in an animal model of Alzheimer’s disease

Cited by 15 publications

References 35 publications

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease

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