Pro- and Anti-inflammatory Effects of High Cholesterol Diet on Aged Brain

Abstract

Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer’s disease. However, their interactive influence on the neurodegenerative progress remains unclear. To address this issue, 6-month-old and 16-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by hippocampus-related functional, pathological, biochemical and molecular analyses. The high cholesterol diet did not exacerbate age-dependent cognitive decline and hippocampal neuronal death, and even greatly mitigated decreases of synaptophysin and growth associated protein 43 expression in the hippocampus of aged mice. Compared with young controls, aged mice fed normal diet showed mild activation of hippocampal microglia with increased expression of CD68, a marker of the microglial M1 phenotype, and decreased expression of CD206, a marker of the microglial M2 phenotype. More interestingly, the high cholesterol diet not only improved NLRP3 inflammasome activation and IL-1β expression, but also increased levels of anti-inflammatory cytokines IL-4 and IL-6 in the hippocampus of old mice, suggesting playing pro- and anti-neuroinflammatory effects. In addition, the cholesterol rich diet resulted in a defect of the blood-brain barrier of aged hippocampus, as revealed by increased brain albumin content. These results have revealed both harmful and protective effects of high cholesterol diet on aged brain, which helps us to understand that hypercholesterolemia in the aged population is not associated with dementia and cognitive impairment.

Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

“…Experimental evidence supports the notion that BBB disruption and further neuroinflammation underlying hypercholesterolemia trigger brain dysfunction ( Ullrich et al, 2010 ; de Oliveira et al, 2014 ; Paul and Borah, 2017 ; Chen et al, 2018 ). Ullrich et al (2010) observed BBB disturbance in the hypercholesterolemic rats’ cortex that was visualized by increased leakage of IgG and microgliosis.…”

“…Mice fed a high cholesterol diet also displayed BBB disruption in brain regions (e.g., the hippocampus, cerebral cortex, SN, and striatum) associated with neuroinflammation (astrogliosis and microgliosis; Paul and Borah, 2017 ; Paul et al, 2017b ). The brain inflammation in rodents fed a high cholesterol diet was also related to increased levels of cytokines such as TNF-α, IL1-α, IL-1β, and IL-6 ( Ullrich et al, 2010 ; Chen et al, 2018 ).…”

Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline

“…Moreover, epidemiological studies showed that diets enriched in cholesterol (HCD) were associated with poor cognitive performance in humans (Requejo et al, 2003). HCD diet also induced impairment of spatial and working memory due to microglial activation and alteration of the BBB integrity in rats (Chen et al, 2018). Interestingly, feeding obese rodents with HFD inhibited the transport through the BBB of neuroendocrine molecules, such as ghrelin and leptin, which promote synaptic plasticity and cognitive functions (Banks et al, 2008; Kanoski et al, 2013; Mainardi et al, 2017).…”

Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

“…Several previous studies suggested that aβ induced the production of inflammatory cytokines, TnFα-and il-1β (21,22), which are important mediators of the inflammatory response in AD (23). These pro-inflammatory cytokines are thought to be responsible for neural death in ad.…”