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Hypercholesterolemia is a known risk factor for Alzheimer's disease (AD). In the present study, we investigated whether diet-induced hypercholesterolemia affects AD-like pathologies such as amyloid β-peptide (Aβ) deposition, tau pathology, inflammation and cognitive impairment, using an Aβ25-35-injected AD-like pathological mouse model. Hypercholesterolemia was induced by providing apolipoprotein E knock out (Apo E KO) mice with a high-fat diet for 4 weeks prior to Aβ25-35 injection and for 4 weeks following Aβ25-35 injection, for a total of 8 weeks of treatment. Our data showed that intracerebroventricular injection of C57BL/6J mice with Aβ25-35 resulted in increased immunoreactivity of Aβ and phosphorylated-tau (p-tau), which was accompanied by enhanced microglial CD11b-like immunoreactivity in the brain. Moreover, hypercholesterolemia slightly increased Aβ and p-tau levels and microglial activation in the vehicle group, while further increasing the Aβ and p-tau levels and microglial activation in Aβ25-35-injected mice. Consistent with the neuropathological analysis, hypercholesterolemia resulted in significant spatial learning and memory deficits in Aβ25-35-injected mice as revealed by water maze testing. Collectively, these findings demonstrated that hypercholesterolemia accelerated Aβ accumulation and tau pathology, which was accompanied by microglial activation and subsequent aggravation of memory impairment induced by Aβ25-35. Thus, we suggest that the modulation of cholesterol can be used to reduce the risk of developing AD.

Atherosclerosis was previously thought to be a disease that primarily involves lipid accumulation in the arterial wall. In this report, we investigated the effect of Viola mandshurica W. Becker (V. mandshurica) water extract on atherosclerosis in apolipoprotein E deficient (ApoE[Formula: see text]) mice. The administration of V. mandshurica to high-fat diet-fed mice reduced body weight, liver weight, and serum levels of lipids (total cholesterol, low-density lipoprotein-cholesterol, triglycerides), glucose, alanine transaminase, and aspartate transaminase. Histopathologic analyses of the aorta and liver revealed that V. mandshurica attenuated atherosclerotic lesions and reduced lipid accumulation, inflammatory responses and fatty acid synthesis. V. mandshurica also increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), thereby reducing acetyl-CoA carboxylase (ACC) in liver tissue and inhibiting sterol regulatory element-binding protein 1c (SREBP-1c). V. mandshurica reduced protein expression levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) as well as ACC, fatty acid synthase, and SREBP-1c. In addition, quantitative analysis of V. mandshurica by high-performance liquid chromatography revealed the presence of esculetin and scopoletin. Esculetin and scopoletin reduced adhesion molecules in human aortic smooth muscle cells. Our results indicate that the anti-atherosclerotic effects of V. mandshurica may be associated with activation of the AMPK pathway. Therefore, AMPK-dependent phosphorylation of SREBP-1c by V. mandshurica may be an effective therapeutic strategy for combatting atherosclerosis and hepatic steatosis.

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BackgroundDo In Seung Gi-Tang (DISGT) is an herbal mixture of traditional Korean medicine that is composed of Rheum undulatum Linne, Prunus Persica (L.) Batsch, Conyza canadensis L., Cinnamomum Cassia Presl, and Glycytthiza uralensis Fischer (8: 6: 4: 4: 4 ratio). We investigated the effect of DISGT on vascular inflammation and lipid accumulation in apolipoprotein E-deficient (ApoE−/−) mice.MethodsApoE−/− mice that were fed a high-fat diet (HFD) were treated with DISGT (300 mg/kg/day) or statin (10 mg/kg/day) for 16 weeks. Serum lipid levels were analyzed. Oil Red O staining was used to evaluate atherosclerotic lesions and lipid accumulation in the aorta and liver, respectively. The expression of adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and E-selectin), fatty acid synthase (FAS), adenosine monophosphate-activated protein kinase (AMPK), and acetyl-coA carboxylase (ACC) in the aorta or liver tissues was measured by western blot analysis. Lipid synthesis and inflammatory responses were assessed by immunohistochemistry and hematoxylin & eosin staining, respectively.ResultsTreatment of HFD-fed mice with DISGT significantly lowered body weight, liver weight, and the levels of lipids, including total cholesterol, low-density lipoprotein-cholesterol, and triglycerides. Glucose levels were also lowered. In the aorta, DISGT attenuated atherosclerotic lesions and reduced the expression of ICAM-1, VCAM-1, and E-selectin. Moreover, DISGT decreased lipid accumulation, inflammatory responses, and FAS levels, and it activated AMPK and reduced ACC expression in liver tissues.ConclusionsThe beneficial, anti-lipolytic, and anti-inflammatory effects of DISGT were mediated by the AMPK pathway. As a result, the expression of inflammatory factors was reduced. Our data provide evidence that DISGT may have strong therapeutic potential in treating vascular diseases, such as atherosclerosis.