Aging triggered Cholesterol loss in hippocampal neurons. Causes and consequences

MAURICIO GERARDO MARTÍN; SIMONA PERGA; LAURA TROVÓ; SILVIA A MENCHÓN; SEBASTIAN MUNCK; CARLOS G DOTTI

Workshop; FEBS/IUBMB Workshop: Eukaryotic Lipids, treasure of regulatory information.; 2010

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 additional mechanisms must have developed to activate TrkB and the downstream pro-survival molecules. We show that age-associated increase in TrkB activity is correlated with a mild yet progressive loss of cholesterol. This, in turn, is 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. Experiments using single molecule tracking of AMPA receptors indicated that cholesterol loss during aging is also accompanied by plasma membrane changes that result in reduced neuronal performance.