Aims: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. Results: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. Innovation and Conclusion: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment. Antioxid. Redox Signal. 23, 695-710.

Deposition of the histone variant H2A.Z by the SWI2/SNF2-Related 1 chromatin remodeling complex (SWR1-C) is important for gene regulation in eukaryotes, but the composition of the Arabidopsis SWR1-C has not been thoroughly characterized. Here, we aim to identify interacting partners of a conserved Arabidopsis SWR1 subunit ACTIN-RELATED PROTEIN 6 (ARP6). We isolate nine predicted components and identify additional interactors implicated in histone acetylation and chromatin biology. One of the interacting partners, methyl-CpG-binding domain 9 (MBD9), also strongly interacts with the Imitation SWItch (ISWI) chromatin remodeling complex. MBD9 is required for deposition of H2A.Z at a distinct subset of ARP6-dependent loci. MBD9 is preferentially bound to nucleosome-depleted regions at the 5’ ends of genes containing high levels of activating histone marks. These data suggest that MBD9 is a SWR1-C interacting protein required for H2A.Z deposition at a subset of actively transcribing genes.

Diabetes mellitus is a significant global public health problem depicting a rising prevalence worldwide. As a serious complication of diabetes, diabetes-associated cognitive decline is attracting increasing attention. However, the underlying mechanisms are yet to be fully determined. Both endoplasmic reticulum (ER) stress and autophagy have been reported to modulate neuronal survival and death and be associated with several neurodegenerative diseases. Here, a streptozotocin-induced diabetic mouse model and primary cultured mouse hippocampal neurons were employed to investigate the possible role of ER stress and autophagy in diabetes-induced neuronal apoptosis and cognitive impairments, and further explore the potential molecular mechanisms. ER stress markers GRP78 and CHOP were both enhanced in diabetic mice, as was phosphorylation of PERK, IRE1α, and JNK. In addition, the results indicated an elevated level of autophagy in diabetic mice, as demonstrated by up-regulated expressions of autophagy markers LC3-II, beclin 1 and down-regulated level of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. Meanwhile, we found that these effects could be abolished by ER stress inhibitor 4-phenylbutyrate or JNK inhibitor SP600125 Furthermore, neuronal apoptosis of diabetic mice was attenuated by pretreatment with 4-phenylbutyrate, while aggravated by application of inhibitor of autophagy bafilomycin A1 These results suggest that ER stress pathway may be involved in diabetes-mediated neurotoxicity and promote the following cognitive impairments. More important, autophagy was induced by diabetes possibly through ER stress-mediated JNK pathway, which may protect neurons against ER stress-associated cell damages.

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Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP), the prominent mediator of the endoplasmic reticulum (ER) stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ-) induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (P < 0.05). The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (P < 0.05). The present results suggested that the CHOP-dependent endoplasmic reticulum (ER) stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment.

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In eukaryotes, DNA wraps around histones to form nucleosomes, which are compacted into chromatin. DNA-templated processes, including transcription, require chromatin disassembly and reassembly mediated by histone chaperones. Additionally, distinct histone variants can replace core histones to regulate chromatin structure and function. Although replacement of H2A with the evolutionarily conserved H2A.Z via the SWR1 histone chaperone complex has been extensively studied, in plants little is known about how a reduction of H2A.Z levels can be achieved. Here, we show that NRP proteins cause a decrease of H2A.Z-containing nucleosomes in Arabidopsis under standard growing conditions. nrp1-1 nrp2-2 double mutants show an over-accumulation of H2A.Z genome-wide, especially at heterochromatic regions normally H2A.Z-depleted in wild-type plants. Our work suggests that NRP proteins regulate gene expression by counteracting SWR1, thereby preventing excessive accumulation of H2A.Z.

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