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.
Résumé
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 pathologieOrigine | Fichiers produits par l'(les) auteur(s) |
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