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MBC in Press, published online ahead of print February 20, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0897

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Submitted on September 13, 2007
Revised on February 6, 2008
Accepted on February 11, 2008

Cholesterol Loss Enhances TrkB Signaling in Hippocampal Neurons Aging in Vitro

Mauricio G. Martin,*{dagger} Simona Perga,*{ddagger} Laura Trovò,{dagger} Andrea Rasola,{sect} Pontus Holm,|| Tomi Rantamäki,¶ Tibor Harkany,# Eero Castrén,¶ Federica Chiara,*{sect} and Carlos G. Dotti{dagger}

{dagger}VIB and Department of Human Genetics, Catholic University of Leuven, B-3000 Leuven, Belgium; {ddagger}Cavalieri Ottolenghi Scientific Institute, Università degli Studi di Torino, 10043 Orbassano (Torino), Italy; {sect}Department of Biomedical Sciences, Università degli Studi di Padova, 35122 Padova, Italy; #Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, and ||Department of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden; Neuroscience Center University of Helsinki, FIN-00014 Helsinki, Finland

Monitoring Editor: Robert Parton

Binding of the neurotrophin 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.

*These authors contributed equally to this work.

Address correspondence to: Federica Chiara (fchiara{at}bio.unipd.it) or Carlos G. Dotti (carlos.dotti{at}med.kuleuven.be)






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