High‑cholesterol diet results in elevated amyloid‑β and oxysterols in rats

Abstract

The aim of the present study was to investigate the effects of diet cholesterol on oxysterol levels and amyloid‑β (Aβ) production in the peripheral blood and the brains of Sprague‑Dawley (SD) rats. SD rats were randomly divided into five groups and fed 0.015, 0.05, 0.2, 0.5 and 1.6% cholesterol‑containing diets for 8 weeks. The effect of the different diets on the levels of cholesterol, oxysterols [including 27‑hydroxycholesterol (OHC), 24S‑OHC, 7α‑OHC and 7β‑OHC], and the Aβ1‑40 and Aβ1‑42 peptides were examined in the plasma and the brain of the rats. The results demonstrated that diet cholesterol increased the levels of plasma cholesterol in a dose‑dependent manner. The plasma levels of 27‑OHC, 7α‑OHC and 7β‑OHC significantly increased in the 0.5 and 1.6% cholesterol diet groups and the brain levels of 27‑OHC significantly increased in the 1.6% cholesterol diet group. Increased concentration of cholesterol in the diet had no significant influence on plasma and brain levels of 24S‑OHC in the rats. In addition, Aβ1‑40 and Aβ1‑42 levels in plasma and brain were significantly elevated following administration of 0.5 and 1.6% diet cholesterol. The present study revealed that high diet cholesterol contributed to increased level of oxysterols, especially 27‑OHC, in the peripheral blood and the brain, which may be the link between increased peripheral cholesterol and brain Aβ production.

Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol

“…In addition, the apolipoprotein E (ApoE) knock-out mice were treated with a high-fat diet and injected intracerebroventricularly with Aβ 25–35 , the results showed that hypercholesterolemia accelerated Aβ accumulation and tau pathology, which subsequently deteriorated cognitive impairment ( Park et al, 2013 ). Similar results were obtained in several different strains of mice and Sprague-Dawley rats, with diet-induced hypercholesterolemia accelerating Aβ accumulation in the brain ( Shie et al, 2002 ; Li et al, 2003 ; Umeda et al, 2012 ; Liu et al, 2018 ). Various animal studies suggest that hypercholesterolemia increases Aβ by affecting APP processing in vivo ( Refolo et al, 2000 ; Ullrich et al, 2010 ).…”

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

“…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.…”

Gut microbiota modulation in Alzheimer's disease: Focus on lipid metabolism

“…Increased levels of 27-hydroxycholesterol (27-OHCE) were observed in the brain of AD patients [31] due to hypercholesterolemia, increased BBB permeability and reduced neuronal metabolism of 27-OHCE by oxysterol 7 a-hydroxylase, a cytochrome p450 enzyme responsible for the first and rate limiting step in bile acid synthesis [32]. Abnormal levels of oxysterols in the brain can increase Ab production [33] and worsen neuroinflammation [34]. In detail, oxysterols are endogenous activators of LXRs, which in turn play a role in the regulation of Ab in the brain by mechanisms involving cholesterol transporters [35].…”