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.
Highlights
Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer’s disease
This hypothesis is supported by epidemiological evidence that hypercholesterolemia has no effect on dementia and cognitive impairment in the elderly [16], and lower serum cholesterol level in the aged populations even increases the risk of Alzheimer’s disease (AD) [17]
The serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected to exam the effectiveness of hypercholesterolemia model (Fig. 1A-C)
Summary
Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer’s disease. A cholesterolenrich diet in the elderly could have a protective effect on the brain function [15], which in turn offsets its negative consequence, especially on the neuroinflammation This hypothesis is supported by epidemiological evidence that hypercholesterolemia has no effect on dementia and cognitive impairment in the elderly [16], and lower serum cholesterol level in the aged populations even increases the risk of AD [17]. In order to define the internal interaction between aging and high cholesterol diet in the development of brain pathology, in the present study, 6-month-old and 16month-old female mice were fed a 3% cholesterol diet for 8 weeks, hippocampus-related spatial cognitive function, synaptic protein levels, glial reactivation, neuroinflammation and pro-inflammatory signal transduction pathway were analyzed
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