Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

Xu, Linhao; Xie, Hui; Shi, Zhihui; Du, Lisheng; Wing, Yun‐Kwok; Li, Albert M.; Ke, Ya; Yung, Wing‐Ho

doi:10.1089/ars.2014.6122

Cited by 81 publications

(87 citation statements)

References 75 publications

(86 reference statements)

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“…The supernatant was centrifuged again at 3500 g for 10 min at 4 °C to obtain the mitochondrial fractions (deposition). Activities of respiratory chain complex I were measured by NADH-ubiquinone oxidoreductase methods [25, 26]. Mitochondria samples (0.5 mg/ml, 20 μl) were added to 165 μl of reaction buffer (50 mM KCl, 10 mM Tris-HCI, 1 mM ethylenediaminetetraacetic acid [EDTA], 2 mM KCN, 5 μM CoQ1) and incubated for 5 min at 30°C.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

Zhou

Lian

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. Methods: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. Results: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. Conclusion: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

Zhou

Lian

Zhang

et al. 2018

Cell Physiol Biochem

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“…; Xu et al . ). Increased ER stress is also associated with the pathogenesis of AD (Salminen et al .…”

Section: Hypoxia Activates γ‐Secretasementioning

confidence: 97%

“…Both hypoxia and ischemia are potent inducers of endoplasmic reticulum (ER) stress in the brain (Xin et al 2014;Xu et al 2015). Increased ER stress is also associated with the pathogenesis of AD (Salminen et al 2009); this might be a consequence of the presence of mild local hypoxia and disturbances in the maintenance of proteostasis.…”

Section: Er Stressmentioning

confidence: 99%

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Salminen

Kauppinen

Kaarniranta

2017

Journal of Neurochemistry

170

124

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Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-b precursor protein (APP) leading to the accumulation of amyloid-b peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of b-and csecretases, whereas a-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1a (HIF-1a) stimulates the transcription of the bsecretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1a protein can directly interact with the c-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate c-secretase. Subsequently, PS1 protein can stabilize HIF-1a protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1a. The activation of b-and c-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that b-and c-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating b-and c-secretases.

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“…These symptoms were associated with pulmonary fibrosis and endothelial apoptosis [4][5][6]. According to previous studies, endoplasmic reticulum (ER) stress activation had been found in IH model and plays a critical role in apoptosis [7,8].…”

Section: Introductionmentioning

confidence: 93%

“…The protocol was well-accepted and utilized by other researchers to generate a sleep apnea model in rodent [8,[23][24][25]. Ordinary cages were placed in computercontrolled ventilation chambers (Oxycycler model A48XOV, Redfield, USA) to achieve IH exposures in the animals.…”

Section: Model Of Chronic Intermittent Hypoxia and Tudca Treatmentmentioning

confidence: 99%

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

Shi

Xie

et al. 2020

BMC Pulm Med

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Background: Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis. Methods: Mice were placed in IH chambers for 4 weeks with an oscillating oxygen (O 2 ) concentration between 5 and 21%, cycling every 90s for 8 h daily. Mice were randomly divided into four groups: control group (normal oxygen), tauroursodeoxycholic acid (TUDCA) group (normal oxygen intraperitoneally injected with TUDCA), IH group and IH + TUDCA group. After 4 weeks, the proteins in three branch signaling pathways of ER stress, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositolrequiring enzyme 1 (IRE-1), were evaluated. The cleaved caspase-3, caspase-12 and TUNNEL staining was assessed. Furthermore, the expression of transforming growth factor-β1 (TGF-β1) and thrombospondin-1(TSP-1), two extracellular matrix proteins that play critical role in fibrosis, were examined. Finally, Masson's trichrome staining was performed to detect the expression of collagen. Results: After 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-β1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins. (Continued on next page)Conclusions: It reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.

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Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

Cited by 81 publications

References 75 publications

Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

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