Neurobiology of Aging 32 (2011) 933–943 Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons Mauricio G. Martin a,∗,1 , Laura Trovò a,1 , Simona Perga b , Agniezska Sadowska a , Andrea Rasola c , Federica Chiara c,d , Carlos G. Dotti a,∗ a VIB Department of Developmental Molecular Genetics and Katholieke Universiteit Leuven Department of Human Genetics, Heerestraat 49, 3000 Leuven, Belgium b Cavalieri Ottolenghi Scientific Institute, Università degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano, TO, Italy c Department of Biomedical Sciences, Università degli Studi di Padova, 35122 Padova, Italy d Department of Environmental Medicine and Public Health, Università degli Studi di Padova, 35122, Padova, Italy Received 26 February 2009; received in revised form 23 April 2009; accepted 30 April 2009 Available online 3 June 2009 Abstract 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. © 2009 Elsevier Inc. All rights reserved. Keywords: Cholesterol; TrkB; Akt; Survival; Stress; CYP46 1. Introduction Ageing is characterized by a decline in cognitive functions such as reduced learning ability and memory. In early reports these deficits were linked to neuronal loss in the hippocam- pus, one of the brain regions where task memory centres are located (Burke and Barnes, 2006; Driscoll et al., 2006; Morrison and Hof, 1997). These observations were consistent with subsequent data suggesting that neuronal death during senescence could be due to the decrease in the availability ∗ Corresponding authors at: VIB/KUL, Heerestraat 49, 3000 Leuven, Belgium. Tel.: +32 163 30 519; fax: +32 163 46 522. E-mail addresses: mauricio.martin@med.kuleuven.be (M.G. Martin), carlos.dotti@med.kuleuven.be (C.G. Dotti). 1 Equal contributing authors. of growth factors (Hattiangady et al., 2005; Mattson and Magnus, 2006; Shetty et al., 2004; Silhol et al., 2005). Con- versely, a plethora of recent evidences show that neuronal density in the hippocampus is unaffected during ageing in both, animal models and humans, despite the decrease in neurotrophin concentration (Burke and Barnes, 2006). This last scenario indicates that post-differentiated neurons must possess a robust and long-term survival strategy to outlive the noxious effects of trophic factor deficiency under the prolonged pressure of multiple stress insults, which act as major determinants of ageing (Andersen, 2004; Balaban et al., 2005; Benn and Woolf, 2004; Schmitt, 2003). The mech- anisms behind survival under such adverse conditions remain largely undefined. The Trk family of receptor tyrosine kinases is one of the better characterized survival-promoter pathways in 0197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2009.04.022