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Cholesterol loss during glutamate-mediated excitotoxicity
Alejandro O Sodero1, Joris Vriens, Debapriya Ghosh
1VIB Center for Biology of Disease, Katholieke Universiteit Leuven, Leuven, Belgium.
The EMBO Journal
|February 21, 2012
Summary
Excitatory neurotransmission, triggered by glutamate, alters brain cholesterol metabolism and neuronal function. This process involves cholesterol 24-hydroxylase (CYP46A1) and impacts calcium signaling in neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Deregulation of brain cholesterol metabolism is linked to neuronal injury and neurodegenerative diseases like Alzheimer's.
- Both conditions involve excessive stimulation of glutamate receptors, suggesting a connection to cholesterol homeostasis.
Purpose of the Study:
- To investigate the role of excitatory neurotransmission in regulating brain cholesterol homeostasis.
- To understand the molecular mechanisms underlying glutamate-mediated cholesterol changes in neurons.
Main Methods:
- Stimulation of glutamatergic neurotransmission in neuronal models.
- Measurement of membrane cholesterol and 24S-hydroxycholesterol levels.
- Gene knockdown of cholesterol 24-hydroxylase (CYP46A1) and assessment of its impact.
- Analysis of intracellular Ca(2+) levels, STIM2 function, and CYP46A1 localization.
Main Results:
- Glutamatergic stimulation caused a significant loss of membrane cholesterol and release of 24S-hydroxycholesterol.
- Knockdown of CYP46A1 prevented glutamate-induced cholesterol loss.
- Cholesterol loss modulated depolarization-evoked calcium responses.
- The process requires high intracellular Ca(2+), functional STIM2, and CYP46A1 mobilization.
Conclusions:
- Excitatory neurotransmission plays a crucial role in controlling brain cholesterol metabolism.
- Cholesterol homeostasis is intrinsically linked to neuronal activity and membrane function.
- Findings provide insights into mechanisms relevant to neurological disorders involving cholesterol deregulation.
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