Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.

Julie Colin (1) , Mélanie Thomas (1) , Lynn Anne Pauron (1) , Anthony Pinçon (1) , Marie-Claire Lanhers (1) , Catherine Corbier (1) , Thomas Claudepierre (1) , Frances T. Yen Potin (1) , Thierry Oster (1) , Catherine Malaplate-Armand (1, 2)

1 URAFPA - Unité de Recherches Animal et Fonctionnalités des Produits Animaux
2 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy

Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents.

Mots clés: Neuronal membranes; Docosahexaenoic acid; Brain aging; Ciliary neurotrophic factor; Dietary lipids; Lipid rafts; Aβ; amyloid-β peptide; AD; Alzheimer's disease; ARA; arachidonic acid; CNTF; ciliary neurotrophic factor; CNTF-R; CNTF receptor; DHA; docosahexaenoic acid; icv; intracerebroventricular; ip; intraperitoneal; PBS; phosphate-buffered saline; PUFA; polyunsaturated fatty acid; StD; standard diet 2 brain aging; dietary lipids; lipid rafts; neuronal membranes

Domaines: Médecine humaine et pathologie

Julie Colin, Mélanie Thomas, Lynn Anne Pauron, Anthony Pinçon, Marie-Claire Lanhers, et al.. Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.. Neurobiology of Aging, 2017, 54, pp.84-93. ⟨10.1016/j.neurobiolaging.2017.02.015⟩. ⟨hal-01595232⟩