Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro.
Binding of the neurotrophin brain-derived neurotrophic factor (BDNF) to the TrkB receptor is a major survival mechanism during embryonic development. In the aged brain, however, BDNF levels are low, suggesting that if TrkB is to play a role in survival at this stage additional mechanisms must have developed. We here show that TrkB activity is most robust in the hippocampus of 21-d-old BDNF-knockout mice as well as in old, wild-type, and BDNF heterozygous animals. Moreover, robust TrkB activity is evident in old but not young hippocampal neurons differentiating in vitro in the absence of any exogenous neurotrophin and also in neurons from BDNF -/- embryos. Age-associated increase in TrkB activity correlated with a mild yet progressive loss of cholesterol. This, in turn, correlated with increased expression of the cholesterol catabolic enzyme cholesterol 24-hydroxylase. Direct cause-effect, cholesterol loss-high TrkB activity was demonstrated by pharmacological means and by manipulating the levels of cholesterol 24-hydroxylase. Because reduced levels of cholesterol and increased expression of choleseterol-24-hydroxylase were also observed in the hippocampus of aged mice, changes in cellular cholesterol content may be used to modulate receptor activity strength in vivo, autonomously or as a way to complement the natural decay of neurotrophin production.
Martin
Mauricio G
MG
VIB and Department of Human Genetics, Catholic University of Leuven, B-3000 Leuven, Belgium.
Perga
Simona
S
Trovò
Laura
L
Rasola
Andrea
A
Holm
Pontus
P
Rantamäki
Tomi
T
Harkany
Tibor
T
Castrén
Eero
E
Chiara
Federica
F
Dotti
Carlos G
CG
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D002784:Cholesterol / Q000172:deficiency*; D000072556:Cholesterol 24-Hydroxylase; D003902:Detergents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology; D008024:Ligands; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D003902:Detergents; D008024:Ligands; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D020813:Receptor, trkB