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High-Fat Diet Alleviates Neuroinflammation and Metabolic Disorders of APP/PS1 Mice and the Intervention With Chinese Medicine.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by the complex interaction of multiple mechanisms. Recent studies examining the effect of high-fat diet (HFD) on the AD phenotype have demonstrated a significant influence on both inflammation and cognition. However, different studies on the effect of high-fat diet on AD pathology have reported conflicting conclusions. To explore the involvement of HFD in AD, we investigated phenotypic and metabolic changes in an AD mouse model in response to HFD. The results indicated there was no significant effect on Aβ levels or contextual memory due to HFD treatment. Of note, HFD did moderate neuroinflammation, despite spurring inflammation and increasing cholesterol levels in the periphery. In addition, diet affected gut microbiota symbiosis, altering the production of bacterial metabolites. HFD created a favorable microenvironment for bile acid alteration and arachidonic acid metabolism in APP/PS1 mice, which may be related to the observed improvement in LXR/PPAR expression. Our previous research demonstrated that Huanglian Jiedu decoction (HLJDD) significantly ameliorated impaired learning and memory. Furthermore, HLJDD may globally suppress inflammation and lipid accumulation to relieve cognitive impairment after HFD intervention. It was difficult to define the effect of HFD on AD progression because the results were influenced by confounding factors and biases. Although there was still obvious damage in AD mice treated with HFD, there was no deterioration and there was even a slight remission of neuroinflammation. Moreover, HLJDD represents a potential AD drug based on its anti-inflammatory and lipid-lowering effects.

SUBMITTER: Fan X

PROVIDER: S-EPMC8217439 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:High-fat diet (HFD)-induced obesity is a risk factor for many metabolic disorders including cardiovascular diseases, diabetes, and fatty liver disease. Although there are accumulating evidences supporting the assumption that regulating gut microbiota as well as its metabolic status is able to mitigate obesity, the inner relationship between the obesity-related gut microbiota and the relevant metabolites are not well defined. In current study, we applied a traditional herbal formula Kang Shuai Lao Pian (KSLP) to HFD-fed mice and evaluated its effect against obesity. Emphases were addressed on identifying profiles of gut microbiota and fecal metabolites with the aid of 16S rRNA gene sequencing and non-target fecal metabolomics techniques. We showed that KSLP could improve HFD-induced obesity, glucose tolerance disorder, as well as gut dysbiosis. In the gut, KSLP corrected the increased abundance of Firmicutes and Proteobacteria, increased ratio of Firmicutes/Bacteroidetes, and decreased abundance of Bacteroidetes caused by HFD. KSLP also reversed HFD-induced significant changes in the abundance of certain genus including Intestinimonas, Oscillibacter, Christensenellaceae_R-7_group, Ruminococcaceae_UCG-010, and Aliihoeflea. Pearson correlation analysis indicated that except for Ruminococcaceae_UCG-010, other four genera had positive correlations with obesity. In addition, 22 key fecal metabolites responding to KSLP treatment were identified. Pearson correlation analysis showed that those metabolites are intimately related to KSLP effective genera of Intestinimonas, Oscillibacter, and Christensenellaceae_R-7_group. Our results indicate that KSLP is a promising traditional Chinese medicine (TCM) applicable for individuals with HFD habit. Intestinimonas, Oscillibacter, and Christensenellaceae_R-7_group might be responsible for the regulatory effect of KSLP. Linking of obesity phenotypes with gut microbiota as well as fecal metabolites is therefore a powerful research strategy to reveal the mechanism of obesity and the targets of intervention.

Project description:AimsAlzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD.MethodsFemale wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining.ResultsRIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well.ConclusionChronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.

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High-Fat Diet Alleviates Neuroinflammation and Metabolic Disorders of APP/PS1 Mice and the Intervention With Chinese Medicine.

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