Effect of Cholesterol Reduction on Receptor Signaling in Neurons [Neurobiology]

September 14th, 2015 by Fukui, K., Ferris, H. A., Kahn, C. R.

Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2 mediated cholesterol synthesis in neuronal and glial cells. In the present study, we have explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-beta-cyclodextrin (MBCD), 2) treatment with the HMG-CoA reductase inhibitor simvastatin and 3) shRNA-mediated knockdown of SREBP2. All three methods produced 20-31% reductions in cellular cholesterol content, similar to the decrease in cholesterol synthesis observed in diabetes. All cholesterol-depleted neuron-derived cells, independent of the method of reduction, exhibited decreased phosphorylation/ activation of IRS-1 and Akt following stimulation by insulin, IGF-1 or the neurotrophins (NGF and BDNF). ERK phosphorylation/activation was also decreased after MBCD and statin treatment, but increased in cells following SREBP2 knockdown. In addition, apoptosis in the presence of amyloid-β; was increased. Reduction in cellular cholesterol also resulted in increased basal autophagy and impairment of induction of autophagy by glucose deprivation. Together, these data indicate that a reduction in neuron-derived cholesterol content, similar to that observed in diabetic brain, creates a state of insulin and growth factor resistance that could contribute to CNS-related complications of diabetes, including increased risk of neurodegenerative diseases such as Alzheimer′s disease.