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Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro.

ABSTRACT: 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.

SUBMITTER: Martin MG

PROVIDER: S-EPMC2366859 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro.

Martin Mauricio G MG 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

Molecular biology of the cell 20080220 5

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 i ...[more]

PMID: 18287532

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Project description:Dysregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental disease. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). In this communication, we examined the effects of lead (Pb(2+)) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. We show that Pb(2+) exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntingtin phosphorylation and protein levels. Combined, these effects of Pb(2+) resulted in decreased concentrations of extracellular mature BDNF. The effect of Pb(2+) on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG-binding protein (MeCP2). TrkB protein levels and autophosphorylation at tyrosine 816 were significantly decreased by Pb(2+) exposure with a concomitant increase in p75 neurotrophin receptor (p75(NTR)) levels and altered TrkB-p75(NTR) colocalization. Finally, phosphorylation of Synapsin I, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb(2+) exposure with no effect on total Synapsin I protein levels. This effect of Pb(2+) exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by us previously (Neal, A. P., Stansfield, K. H., Worley, P. F., Thompson, R. E., and Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of N-Methyl-D-aspartate receptor (NMDAR) dependent BDNF signaling. Toxicol. Sci. 116, 249-263) because it controls vesicle movement from the reserve pool to the readily releasable pool. In summary, the present study demonstrates that Pb(2+) exposure during the period of synaptogenesis of hippocampal neurons in culture disrupts multiple synaptic processes regulated by BDNF-TrkB signaling with long-term consequences for synaptic function and neuronal development.

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Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro.

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Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro.

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