27-Hydroxycholesterol-Induced Dysregulation of Cholesterol Metabolism Impairs Learning and Memory Ability in ApoE ε4 Transgenic Mice
| Autor: | Yushan Wang, Ling Hao, Tao Wang, Wen Liu, Lijing Wang, Mengwei Ju, Wenjing Feng, Rong Xiao |
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| Rok vydání: | 2022 |
| Předmět: |
Memory Disorders
Amyloid beta-Peptides Apolipoprotein A-I Organic Chemistry Apolipoprotein E4 Mice Transgenic General Medicine Anastrozole Catalysis Hydroxycholesterols Computer Science Applications Inorganic Chemistry Ligases Lipoproteins LDL Mice Inbred C57BL Mice Apolipoproteins E Cholesterol Alzheimer Disease Animals Physical and Theoretical Chemistry Molecular Biology 27-hydroxycholesterol cholesterol metabolism homeostasis learning and memory impairment transgenic mice Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 19; Pages: 11639 |
| ISSN: | 1422-0067 |
| Popis: | Dysregulated brain cholesterol metabolism is one of the characteristics of Alzheimer’s disease (AD). 27-Hydroxycholesterol (27-OHC) is a cholesterol metabolite that plays an essential role in regulating cholesterol metabolism and it is suggested that it contributes to AD-related cognitive deficits. However, the link between 27-OHC and cholesterol homeostasis, and how this relationship relates to AD pathogenesis, remain elusive. Here, 12-month-old ApoE ε4 transgenic mice were injected with saline, 27-OHC, 27-OHC synthetase inhibitor (anastrozole, ANS), and 27-OHC+ANS for 21 consecutive days. C57BL/6J mice injected with saline were used as wild-type controls. The indicators of cholesterol metabolism, synaptic structure, amyloid β 1-42 (Aβ1-42), and learning and memory abilities were measured. Compared with the wild-type mice, ApoE ε4 mice had poor memory and dysregulated cholesterol metabolism. Additionally, damaged brain tissue and synaptic structure, cognitive decline, and higher Aβ1-42 levels were observed in the 27-OHC group. Moreover, cholesterol transport proteins such as ATP-binding cassette transporter A1 (ABCA1), apolipoprotein E (ApoE), low-density lipoprotein receptor (LDLR), and low-density lipoprotein receptor-related protein1 (LRP1) were up-regulated in the cortex after the 27-OHC treatment. The levels of cholesterol metabolism-related indicators in the hippocampus were not consistent with those in the cortex. Additionally, higher serum apolipoprotein A1 (ApoA1) levels and lower serum ApoE levels were observed in the 27-OHC group. Notably, ANS partially reversed the effects of 27-OHC. In conclusion, the altered cholesterol metabolism induced by 27-OHC was involved in Aβ1-42 deposition and abnormalities in both the brain tissue and synaptic structure, ultimately leading to memory loss in the ApoE ε4 transgenic mice. |
| Databáze: | OpenAIRE |
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