Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons.
Aged neurons constitute an outstanding example of survival robustness, outliving the accumulation of reactive oxygen species (ROS) derived from various physiological activities. Since during aging hippocampal neurons experience a progressive loss of membrane cholesterol and, by virtue of this, a gradual and sustained increase in the activity of the survival receptor tyrosine kinase TrkB, we have tested in this study if cholesterol loss is functionally associated to survival robustness during aging. We show that old neurons that did not undergo the cholesterol drop, upon knockdown of the cholesterol hydroxylating enzyme Cyp46, presented low TrkB activity and increased apoptotic levels. In further agreement, inducing cholesterol loss in young neurons led to the early appearance of TrkB activity. In vivo, Cyp46 knockdown led to the appearance of damaged hippocampal neurons in old mice exposed to exogenous stressful stimuli. Cholesterol loss seems therefore to contribute to neuronal survival in conditions of prominent stress, either acute or chronic. The relevance of this pathway in health and disease is discussed.
Martin
Mauricio G
MG
VIB Department of Developmental Molecular Genetics and Katholieke Universiteit Leuven Department of Human Genetics, Heerestraat 49, 3000 Leuven, Belgium. mauricio.martin@med.kuleuven.be
Trovò
Laura
L
Perga
Simona
S
Sadowska
Agniezska
A
Rasola
Andrea
A
Chiara
Federica
F
Dotti
Carlos G
CG
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D020813:Receptor, trkB