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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

[ Vol. 15 , Issue. 7 ]

Author(s):

Naima Chalour*, Agathe Maoui, Patrice Rat, France Massicot, Melody Dutot, Anne-Marie Faussat, Estelle Devevre, Astrid Limb, Jean-Michel Warnet, Jacques Treton, Virginie Dinet and Frederic Mascarelli*   Pages 643 - 654 ( 12 )

Abstract:


Background: Alzheimer's disease (AD) and age-related macular degeneration (AMD) present similarities, particularly with respect to oxidative stress, including production of 4-Hydroxy-2- nonenal (HNE). AMD has been named the AD in the eye. The Müller cells (MC) function as a principal glia of the retina and maintain water/potassium, glutamate homeostasis and redox status. Any MC dysfunction results in retinal neurodegeneration.

Objectives: We investigated the effects of HNE in human MC.

Results: HNE induced an increase of the reactive oxygen species associated with mitochondrial dysfunction and apoptosis. HNE induced endoplasmic reticulum (ER) stress (upregulation of GRP78/Bip, and the proapoptotic factor, CHOP). HNE also impaired expression of genes controlling potassium homeostasis (KCNJ10), glutamate detoxification (GS), and the visual cycle (RLBP1). MC adaptive response to HNE included upregulation of amyloid-β protein precursor (AβPP). To determine the role of AβPP, we overexpressed AβPP in MC. Overexpression of AβPP induced strong antioxidant and anti-ER stress (PERK downregulation and GADD34 upregulation) responses accompanied by activation of the prosurvival branch of the unfolded protein response. It was also associated with upregulation of major genes involved in MC-controlled retinal homeostasis (KCNJ10, GS, and RLBP1) and protection against HNE-induced apoptosis. Therefore, AβPP is an ER and oxidative stress responsive molecule, and is able to stimulate the transcription of major genes involved in MC functions impaired by HNE.

Conclusion: 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.

Keywords:

AβPP, oxidative stress, glial cells, Alzheimer's disease, Age related macular degeneration, retina.

Affiliation:

Universite des Sciences et Technologies d`Alger, laboratoire de Neurochimie/LBPO, FSB/USTHB, Alger, Centre de Recherche des Cordeliers, Universite Paris Descartes, UMRS1138, Paris, F-75006, Faculte de Pharmacie de Paris, Toxicology lab UMR CNRS 8638, Universite Paris Descartes, Sorbonne Paris Cite, F-75006 Paris, Faculte de Pharmacie de Paris, Toxicology lab UMR CNRS 8638, Universite Paris Descartes, Sorbonne Paris Cite, F-75006 Paris, Faculte de Pharmacie de Paris, Toxicology lab UMR CNRS 8638, Universite Paris Descartes, Sorbonne Paris Cite, F-75006 Paris, IFR65, Institut de Recherche en Sante, Paris, F-75012, Centre de Recherche des Cordeliers, Universite Paris Descartes, UMRS1138, Paris, F-75006, University College London, Institute of Ophthalmology and Moorfields Eye Hospital, London, Faculte de Pharmacie de Paris, Toxicology lab UMR CNRS 8638, Universite Paris Descartes, Sorbonne Paris Cite, F-75006 Paris, Centre de Recherche des Cordeliers, Universite Paris Descartes, UMRS1138, Paris, F-75006, Centre de Recherche des Cordeliers, Universite Paris Descartes, UMRS1138, Paris, F-75006, Centre de Recherche des Cordeliers, Universite Paris Descartes, UMRS1138, Paris, F-75006



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