IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
Cellular stress from excitatory neurotransmission contributes to cholesterol loss in hippocampal neurons aging in vitro
Autor/es:
SODERO AO, .; WEISSMANN C, ; LEDESMA MD, ; DOTTI CG
Revista:
NEUROBIOLOGY OF AGING
Editorial:
ELSEVIER SCIENCE INC
Referencias:
Año: 2011 vol. 32 p. 1043 - 1053
ISSN:
0197-4580
Resumen:
After approximately 3 weeks in vitro, hippocampal neurons present many of the
typical hallmarks accompanying neuronal aging in vivo, including accumulation of
reactive oxygen species (ROS), lipofuscin granules, heterochromatic foci, and
activation of the Jun N-terminal protein kinase (pJNK) and p53/p21 pathways. In
addition, hippocampal neurons in vitro undergo a gradual loss of cholesterol,
which is important for the activation of the prosurvival tyrosine kinase
receptor TrkB. Here, we used the hippocampal in vitro system to investigate the
possible cause of age-accompanying cholesterol loss. We report that cholesterol
loss during in vitro aging is paralleled by upregulation and translocation to
the neuronal surface of cholesterol-24-hydroxylase (Cyp46), the enzyme
responsible for cholesterol removal from neurons. Chronic reduction of
electrical activity diminished cholesterol loss in aged neurons and precluded
the upregulation of cholesterol-24-hydroxylase. In agreement with a cause-effect
relationship, stimulation of excitatory neurotransmission in young neurons led
to cholesterol loss. Mechanistically, N-methyl-D-aspartate (NMDA)-mediated
excitatory neurotransmission leads to cholesterol loss through generation of
reactive oxygen species derived from the activation of the stress-responsive
enzyme NADPH oxidase. Supporting the relevance of the in vitro data, reduced
cholesterol was also detected in synaptic membranes from old mice brains.
Furthermore, excitatory neurotransmission via the nicotinamide adenine
dinucleotide phosphate (NADPH)-oxidase pathway induced cholesterol loss in
purified brain synaptosomes. The current studies highlight excitatory
neurotransmission as 1 of the mechanisms involved in cholesterol loss during
aging.