Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling.

Abstract

Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-β hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid β and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.

• Authors: Ting Liu, Yang Li, Baoyu Yang, Haozhen Wang, Chen Lu, Alan K Chang, Xiuting Huang, Xiujin Zhang, Ziyin Lu, Xiuli Lu, Bing Gao
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 17 Issue 14 Pg. 3702-3716 ( 2021) ISSN: 1449-2288 [Electronic] Australia
• PMID: 34671194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Androstenes
• Nerve Tissue Proteins
• insulin-like growth factor-1, rat
• 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
• Insulin-Like Growth Factor I
• Cholesterol
• DHCR24 protein, rat
• Oxidoreductases Acting on CH-CH Group Donors
• Proto-Oncogene Proteins c-akt

Topics

• Androstenes (pharmacology)
• Animals
• Brain (physiology)
• Cholesterol (biosynthesis)
• Insulin-Like Growth Factor I (metabolism)
• Maze Learning
• Nerve Tissue Proteins (antagonists & inhibitors, genetics)
• Neurons (drug effects, metabolism)
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, genetics)
• PC12 Cells
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Signal Transduction (physiology)