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

Neurobiol Aging. 2017 Jun:54:84-93. doi: 10.1016/j.neurobiolaging.2017.02.015. Epub 2017 Mar 3.


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.

Keywords: Brain aging; Ciliary neurotrophic factor; Dietary lipids; Docosahexaenoic acid; Lipid rafts; Neuronal membranes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / physiology*
  • Animals
  • Brain / cytology*
  • Cell Membrane / physiology*
  • Ciliary Neurotrophic Factor / physiology
  • Dietary Fats, Unsaturated
  • Docosahexaenoic Acids
  • MAP Kinase Signaling System / physiology
  • Male
  • Membrane Microdomains
  • Mice, Inbred C57BL
  • Neurons / cytology*
  • Nootropic Agents / therapeutic use*
  • Receptor, Ciliary Neurotrophic Factor / physiology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction


  • Ciliary Neurotrophic Factor
  • Dietary Fats, Unsaturated
  • Nootropic Agents
  • Receptor, Ciliary Neurotrophic Factor
  • STAT3 Transcription Factor
  • Docosahexaenoic Acids