Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

Zhang, Xiaona; Lv, Chenyan; An, Yu; Liu, Quanri; Rong, Hongguo; Tao, Lingwei; Wang, Ying; Wang, Yushan; Xiao, Rong

doi:10.1002/mnfr.201700531

Cited by 39 publications

(29 citation statements)

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“…Our recent studies showed the toxic effect of 27-OHC in C6 glioma cells and in the brains of Sprague-Dawley rats fed a high-cholesterol diet. Our results suggest that 27-OHC may be able to inhibit cholesterol synthesis in the brain Zhang et al, 2018). In addition to being involved in cholesterol metabolism, 27-OHC is also involved in the inflammatory process.…”

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confidence: 69%

NF‐κB‐mediated inflammatory damage is differentially affected in SH‐SY5Y and C6 cells treated with 27‐hydroxycholesterol

Zhao

et al. 2019

Food Science & Nutrition

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Previous studies have demonstrated that 27‐hydroxycholesterol (27‐OHC), a cholesterol metabolite, was involved in the inflammatory process of Alzheimer's disease (AD). The present study aimed to investigate the 27‐OHC‐induced inflammatory damage to neurons and astrocytes and the underlying mechanism(s) accounting for this damage. Human neuroblastoma cells (SH‐SY5Y cells) and rat glioma cells (C6 cells) were treated with vehicle or 27‐OHC (5, 10, or 20 μM) for 24 hr. The levels of secreted interleukin‐1β (IL‐1β), interleukin‐10 (IL‐10), tumor necrosis factor alpha (TNF‐α), and inducible nitric oxide synthase (iNOS) were determined by using an enzyme‐linked immunosorbent assay (ELISA). Immunofluorescence staining was used to determine the cellular expression of toll‐like receptor 4 (TLR4) and transforming growth factor‐β (TGF‐β). The mRNA and protein expression levels of nuclear factor‐κB p65 (NF‐κB p65), nuclear factor‐κB p50 (NF‐κB p50) and cyclooxygenase‐2 (COX‐2) in both SH‐SY5Y and C6 cells were also detected by real‐time PCR and Western blot, respectively. The results of this study showed that 27‐OHC treatment increased secretion of TNF‐α and iNOS and decreased secretion of IL‐10, upregulated expression of TGF‐β, NF‐κB p65 and p50, and downregulated expression of COX‐2 in SH‐SY5Y cells. In C6 cells, treatment with 27‐OHC resulted in decreased secretion of IL‐1β, IL‐10, TNF‐α, and iNOS, and increased expression of TLR4 and TGF‐β. These results suggest that 27‐OHC may cause inflammatory damage to neurons by activating the TGF‐β/NF‐κB signaling pathway and to astrocytes by activating the TLR4/TGF‐β signaling, which results in the subsequent release of inflammatory cytokines.

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confidence: 69%

NF‐κB‐mediated inflammatory damage is differentially affected in SH‐SY5Y and C6 cells treated with 27‐hydroxycholesterol

Zhao

et al. 2019

Food Science & Nutrition

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“…In this case, production, transport and elimination of Aβ may play key roles in Aβ pathology of MCI patients. While several studies including ours have manifested that the accumulation of Aβ in brain may be associated with the disturbance of 27‐OHC in brain and/or circulation , the underling mechanisms in the correlation between oxysterols and Aβ are still unclear. The second aim of this study is to investigate the molecular mechanism of excessive oxysterols on regulating Aβ metabolism.…”

Section: Introductionmentioning

confidence: 86%

“…The reactions were under the following conditions: 95°C for 10 minutes, 40 cycles of 95°C for 10 s, 60°C for 20 s and 72°C for 10 s. RNU6B was used as the internal standard. For gene expression analysis, 1 μg total RNA was used as template to synthesize cDNA and further subjected to qRT‐PCR reaction as described elsewhere . GAPDH served as an internal reference for normalization.…”

Section: Methodsmentioning

confidence: 99%

“…Protein expressions of Aβ metabolism index (APP, BACE1, ADAM10, LRP1, RAGE, NEP, IDE) were tested by western blot as described previously . Brain tissue was homogenized in a lysis buffer containing protease inhibitor (1 mM PMSF) and centrifuged at 15,000 rpm for 20 minutes at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Spatial learning and memory capability of mice were assessed by the Morris water maze (MWM) test as described previously . Briefly, an escape platform (38 cm in height, 10 cm in diameter) was submerged on a white‐water tank (temperature 21 ± 1°C) and located at a constant position in the middle of the southwest quadrant.…”

Section: Methodsmentioning

confidence: 99%

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27‐hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice

Zhang

et al. 2019

Brain Pathology

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The oxysterol 27-hydroxycholesterol (27-OHC) has been considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Because β-amyloid peptide (Aβ) is the pathological hallmark of AD, the aim of this study is to verify whether 27-OHC could lead to cognitive impairment through modulating Aβ accumulation and deposition. Regulation of Aβ metabolism was explored as the pathogenic mechanism of 27-OHC. Furthermore, microRNAs (miRNAs) and their relations with 27-OHC were also detected. In present study, matched case-control study and APP/PS1 transgenic mice research were conducted. The results showed that the 27-OHC and Aβ in plasma were increased in mild cognitive impairment patients, and a slight correlation was found between 27-OHC and Aβ1-40. This relationship was also proved by the research of APP/PS1 mice. More severe learning and memory impairment and higher Aβ1-40 expression in brain and plasma were detected in the APP/PS1 mice of 27-OHC treatment group. In addition, increased amyloid plaques were also found in the hippocampus of 27-OHC-treated mice. In order to find out the mechanism of 27-OHC on regulating Aβ metabolism, the factors of Aβ production (APP, BACE1 and ADAM10), transport (LRP1 and RAGE) and elimination (NEP and IDE) were tested respectively. The gene and protein expressions of APP, BACE1 and RAGE were increased while LRP1 and IDE were decreased in the brain of 27-OHC-treated mice. At last, down-regulated expression of miRNA let-7g-5p was found after 27-OHC treatment. In conclusion, these findings suggested that excessive 27-OHC could enhance the accumulation and deposition of Aβ both in brain and blood, resulting in a severe impairment of cognition, especially in the modulation of Aβ1-40. The mechanism might be associated with the regulation of Aβ metabolism, and miRNA let-7g-5p was likely to play a vital role in this pathological process induced by 27-OHC.Brain Pathology 29 (2019) 558-573

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Plasma oxysterols are associated with serum lipids and dementia risk in older women

Dunk,

Rapp,

Hayden

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONApolipoprotein E4 (APOE4) carriers’ tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood‐brain barrier.METHODSRelationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment.RESULTSLevels of 24(S)‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), and 24‐OHC/27‐OHC ratio did not differ by APOE status (p’s > 0.05). Higher 24‐OHC and 27‐OHC were associated with higher total, low density lipoprotein (LDL), non‐high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p’s < 0.05). Higher 24‐OHC/27‐OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02‐2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers.DISCUSSIONLess favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24‐OHC/27‐OHC may contribute to dementia risk in APOE3 and APOE4+ carriers.

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Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

Abstract: This study indicates that the mechanisms of dietary cholesterol on learning and memory impairment may be involved in cholesterol metabolism and lysosome function with the increase of plasma 27-OHC, thus resulting in Aβ formation and accumulation.

Cited by 39 publications

References 44 publications

NF‐κB‐mediated inflammatory damage is differentially affected in SH‐SY5Y and C6 cells treated with 27‐hydroxycholesterol

NF‐κB‐mediated inflammatory damage is differentially affected in SH‐SY5Y and C6 cells treated with 27‐hydroxycholesterol

27‐hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice

Plasma oxysterols are associated with serum lipids and dementia risk in older women

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