High cholesterol‐induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice

Abstract

Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer’s disease (AD)-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of AD pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory (WM) load compared to counterparts receiving a control diet while the hypercholesterolemic LDLR−/− mice showed impaired WM regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR−/− mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including TNFα, IL-1β, IL-6, NOS2 and COX2. There was also an induced expression of the key APP processing enzyme i.e., BACE1 in both high fat/cholesterol-fed C57BL/6 and LDLR−/− mice accompanied by an increased generation of C-terminal fragments (CTFs) of APP. Although ELISA for Aβ failed to record significant changes in the non-transgenic mice, a 3-fold increase in Aβ-40 accumulation was apparent in a strain of transgenic mice expressing wt hAPP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.

Exercise Is More Effective than Diet Control in Preventing High Fat Diet-induced β-Amyloid Deposition and Memory Deficit in Amyloid Precursor Protein Transgenic Mice

“…This up-regulation increases soluble A␤ oligomers as well as deposited A␤ levels followed by memory deficit (7). The up-regulation of ␤-secretase was also reported in HFD-feeding mice from another laboratory (32) and consistently reported in AD cases by several previous studies (33)(34)(35). Thus, this phenomenon might represent the actual pathology of sporadic AD.…”

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

“…It is well known that hyperlipidemia induces inflammation in the brain [5][6][7] and that hyperlipidemia exacerbates the ischemic brain damage that is linked to neuroinflammation [8,9] . There is also considerable evidence that hyperlipidemia contributes to the disruption of cerebrovascular reflexes and the breakdown of the blood-brain barrier [45,46] .…”

“…Although hyperlipidemia is not a direct predictor of stroke, half of stroke patients have hyperlipidemia [4] . Hyperlipidemia induces inflammation in the brain [5][6][7] and exacerbates ischemic brain damage [8,9] . Therefore, decreasing cholesterol and inflammation may be an effective therapeutic strategy for reducing the influences of both hyperlipidemia and ischemic stroke.…”

Effect of Cholesterol Enriched or Fatty-Acid Diets on Cholesterol and Lipid Levels in Young Wistar Rats

“…Elevated levels of cholesterol have been proposed as one of the midlife risk factors for developing Alzheimer's disease [2]. It has been shown that hypercholesterolemia induced by diet can produce neuroinflammation accompanied by cognitive deficit as well as changes in the processing of amyloid precursor protein (APP) one of the markers associate to Alzheimer's disease in C57BL/6 mice [3]. In apolipoprotein E ε3 and ε4 knock-in mice 44 -45 weeks of cholesterol enriched diet increases levels of brain cholesterol esters especially in APOE ε4 knock-in mice [4].…”