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

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 08/2008; 106(1):475-85. DOI: 10.1111/j.1471-4159.2008.05415.x
Source: PubMed


Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease-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 Alzheimer's disease 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 load compared with counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired working memory 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 tumor necrosis factor-alpha, interleukin-1beta and -6, nitric oxide synthase 2, and cycloxygenase 2. There was also an induced expression of the key APP processing enzyme i.e. beta-site APP cleaving enzyme 1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments of APP. Although ELISA for beta-amyloid failed to record significant changes in the non-transgenic mice, a threefold increase in beta-amyloid 40 accumulation was apparent in a strain of transgenic mice expressing wild-type human APP 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.

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Available from: Kumar Sambamurti, Oct 24, 2014
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    • "In particular, it was demonstrated that a diet enriched with saturated and trans fatty acids is associated with increased risk for AD (Kalmijn et al., 1997; Luchsinger et al., 2002; Morris et al., 2003). Biological mechanisms underlying damaging effects of obesity on brain are still poorly understood, although studies on experimental models and humans have shown that obesity is associated with increased brain oxidative stress (Mattson et al., 2003; Zhang et al., 2005; Souza et al., 2007) and neuroinflammation (Thirumangalakudi et al., 2008; Pistell et al., 2010; Freeman et al., 2014), both implicated in the pathogenesis of neurodegenerative diseases (Freeman et al., 2014). Therefore, the identification of molecules that can be modulated by dietary fats, might contribute to clarify the specific obesity-related effects on brain physiology and pathology. "
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    • "Obesity is a disease in which low grade inflammation is described at the periphery both in humans and rodent models (Clement et al., 2004; Cottam et al., 2004; Everard and Cani, 2013). In rodents, obesity-induced inflammation is also described at the brain level and, of interest for spatial memory, in the hippocampus (Dinel et al., 2011; Lu et al., 2011; Thirumangalakudi et al., 2008). In the present study, we do not find any effects of HFD exposure on peripheral or brain pro-inflammatory cytokines production at basal state. "
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