AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

Chalour, Naima; Maoui, Agathe; Rat, Patrice; Massicot, France; Dutot, Mélody; Faussat, Anne-Marie; Devêvre, Estelle; Limb, Astrid; Warnet, Jean‐Michel; Tréton, Jacques; Dinet, Virginie; Mascarelli, Frédéric

doi:10.2174/1567205015666180119101832

Cited by 6 publications

(4 citation statements)

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“…Glial cell activation is one of the pathological manifestations of AD ( 26 ). It has been suggested that the activation of glial cells may contribute to Aβ release ( 27 ), resulting in neuronal dysfunction and neuroinflammation, leading to the progression of AD ( 28 ). Immunohistochemistry staining results in the present study demonstrated that the increased Iba1 and GFAP expression in the hippocampus of 3xTg mice was reversed by SSD treatment, suggesting that microglia and astrocyte activation was reduced.…”

Section: Discussionmentioning

confidence: 99%

Cognitive improvements and reduction in amyloid plaque deposition by saikosaponin D treatment in a murine model of Alzheimer's disease

et al. 2020

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Alzheimer's disease (AD), is a severe neurodegenerative disease that currently lacks an optimally effective therapeutic agent for its management. Saikosaponin D (SSD) is a component extracted from the herb Bupleurum falcatum that is commonly used in Chinese medicine. Although SSD has been reported to exert neuroprotective effects, its pharmacological role in AD has not been previously elucidated. Therefore, the aim of the present study was to investigate whether SSD treatment improves the cognitive function and pathological features of 3xTg mice, a triple-transgenic mouse model of AD that displays classical pathological features of AD. The effects of SSD treatment on the behavioral, histological and physiological features of the animal were quantified. Results from the behavioral experiments on the SSD-treated 3xTg mice identified a significant reduction in memory impairment. In addition, histological staining results indicated that SSD application could preserve the morphology of neurons, reduce apoptosis and significantly inhibit amyloid-β deposition in the hippocampus of 3xTg mice. SSD treatment also decelerated the activation of microglia and astrocytes in the hippocampus of 3xTg mice, possibly via the inhibition of the NF-κB signal transduction pathway. Therefore, the present study demonstrated the protective effects of SSD against progressive neurodegeneration and identified the potential underlying pharmacological mechanism. It was speculated that SSD may serve as a possible therapeutic agent in AD treatment in the future.

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Section: Discussionmentioning

confidence: 99%

Cognitive improvements and reduction in amyloid plaque deposition by saikosaponin D treatment in a murine model of Alzheimer's disease

et al. 2020

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“…In response to ER stress, the MG exerts a protective role by upregulating AβPP to defend against apoptosis and recover functional gene transcription. 269 Interestingly, AβPP is proven to be harmful in neovascularization AMD, as mentioned before. These data seem to convey that AβPP is a dual regulator of cell survival dependent on VEGF expression level.…”

Section: Er Stress and Age-related Macular Degenerationmentioning

confidence: 78%

“…[266][267][268] These risk factors can induce ER stress in AMD models. [269][270][271] Research has revealed that different metabolic pathways, including the cholesterol pathway, retinoid metabolism, and lipid metabolism, are involved in drusen accumulation, neovascularization, and subretinal fibrosis via ER stress. We elaborate on the role of ER stress in the formation of AMD and its targeted treatment (Fig.…”

Section: Er Stress and Age-related Macular Degenerationmentioning

confidence: 99%

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Chen,

Shi,

et al. 2023

Sig Transduct Target Ther

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The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.

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“…GRP78/BiP can also prompt the process of Müller cells, which are responsible for the retinal metabolism through the UPR, as shown in diabetic retinopathy. 60 , 61 Also, the activation and migration of Müller cells in LIRD have been confirmed to modulate the apoptotic loss of photoreceptor cells in the outer retina. 62 TEM in the present work also revealed that broadened Müller cell processes intervened in the space between photoreceptor somas, indicating metabolic modulation in the degenerative retina and engulfing and clearing of the damaged photoreceptor.…”

Section: Discussionmentioning

confidence: 97%

Effects of Different Spectrum of LEDs on Retinal Degeneration Through Regulating Endoplasmic Reticulum Stress

Chen

Lin

Xiao

et al. 2023

Trans. Vis. Sci. Tech.

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Purpose To evaluate the impact of full-spectrum light-emitting diodes (LEDs) on albino guinea pigs’ retina and investigate the roles of short-wavelength opsin (S-opsin) and endoplasmic reticulum (ER) stress in light-induced retinal degeneration (LIRD). Methods Three-week-old albino guinea pigs ( n = 30) were distributed into five groups under 12/12 light/dark cycles with indoor natural light (NC; 300–500 lux, n = 6), full-spectrum LEDs (FL; 300 lux, n = 6; 3000 lux, n = 6), and commercial cold-white LEDs (CL; 300 lux, n = 6; 3000 lux, n = 6) and raised for 28 days. Hematoxylin and eosin staining and transmission electron microscopy evaluated the morphological changes of retinas. The immunofluorescence and real-time quantitative polymerase chain reaction (RT-qPCR) measured the expression and content of S-opsin and ER stress-related genes and proteins. Results We found that albino guinea pigs exposed to FL at either 300 lux or 3000 lux developed less severe retinal morphological damage than animals exposed to the CL light, which emerged as a significant characteristic of LIRD. Meanwhile, the damage on the ventral retina was more serious, mainly due to its ability to absorb the blue light in the LEDs more easily. Compared to the FL-exposed groups, the CL light increased the aggregation of S-opsin and the expression of ER stress-related factors. Conclusions Commercial cold-white LEDs can induce ER stress and unfolded protein response in LIRD, and full-spectrum LED attenuates LIRD by regulating ER stress in albino guinea pig retinas in vivo. Translational Relevance Full-spectrum LEDs offer specific eye protection and eye adaptability that can well replace commercial cold-white LEDs in both clinical practice and research. It should be further developed for lighting used in health care facilities.

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AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

Abstract: Our study suggests that targeting oxidative and ER stress might be a potential therapeutic strategy against glia impairment in AMD and AD, in light of the common features between the two pathologies.

Cited by 6 publications

References 48 publications

Cognitive improvements and reduction in amyloid plaque deposition by saikosaponin D treatment in a murine model of Alzheimer's disease

Cognitive improvements and reduction in amyloid plaque deposition by saikosaponin D treatment in a murine model of Alzheimer's disease

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Effects of Different Spectrum of LEDs on Retinal Degeneration Through Regulating Endoplasmic Reticulum Stress

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