Targeting demyelination via α-secretases promoting sAPPα release to enhance remyelination in central nervous system

Gemma Llufriu-Dabéna,1, Alex Carretea,1, Elena Chiertoa, Jo Mailleuxb, Emeline Camanda, Anne Simona, Tim Vanmierlob, Christiane Rosec, Bernadette Allinquantc, Jerome J.A. Hendriksb, Charbel Massaada, Delphine Meffrea,2, Mehrnaz Jafarian-Tehrania,⁎,2

a  / INSERM UMR-S 1124, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, 75006 Paris, France
b  / Biomedisch Onderzoeksinstituut, Universiteit Hasselt, Campus Diepenbeek, Agoralaan Gebouw C, B-3590 Diepenbeek, Belgium
c /  INSERM UMR-S 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 102-108 rue de la santé, 75014 Paris, France


Abstract


Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5 weeks. To test the protective effect and the remyelination potential of etazolate, an α-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPα in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr+ adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an α- secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPα treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPα release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPα release in demyelinating disorders.


This part of the website could either be in French or English, depending on the sources of the actualities.

Autres Publications

 13 février 2019
A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine
 11 février 2019
Live Tracking of Inter-organ Communication by Endogenous Exosomes In Vivo
 06 février 2019
Mitochondria, Metabolism, and Redox Mechanisms in Psychiatric Disorders
 09 janvier 2019
In vivo Optogenetic Approach to Study Neuron-Oligodendroglia Interactions in Mouse Pups
 21 décembre 2018
Predictive Modulation of Corticospinal Excitability and Implicit Encoding of Movement Probability in Schizophrenia
 07 novembre 2018
Manual Dexterity and Aging: A Pilot Study Disentangling Sensorimotor From Cognitive Decline
 05 novembre 2018
Burnout in medical students before residency: A systematic review and meta-analysis
 03 octobre 2018
Tobacco Smoking and Psychotic-Like Experiences in a General Population Sample
 14 juin 2018
The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse
 07 juin 2018
a2- and b2-Adrenoreceptor-Mediated Efficacy of the Atypical Antidepressant Agomelatine Combined With Gabapentin to Suppress Allodynia in Neuropathic Rats With Ligated Infraorbital or Sciatic Nerve
 18 mai 2018
Memory circuits: CA2
 07 mai 2018
Cortical developmental death: selected to survive or fated to die
 05 avril 2018
Plasma amyloid levels within the Alzheimer’s process and correlations with central biomarkers
 02 mars 2018
Longitudinal Analyses of Blood Transcriptome During Conversion to Psychosis.
 15 février 2018
Mapping molecular assemblies with fluorescence microscopy and object-based spatial statistics
 14 février 2018
A disassembly-driven mechanism explains F-actin-mediated chromosome transport in starfish oocytes
 12 décembre 2017
The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome.
 24 novembre 2017
Lentiviral vector-driven inhibition of 5-HT synthesis in B3 bulbo-spinal serotonergic projections – Consequences on nociception, inflammatory and neuropathic pain in rats
 04 octobre 2017
Stroke
 20 septembre 2017
Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties