Abstract
Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways.
Highlights
Previous studies have shown that elevated blood lipids and a diet high in saturated fats puts individuals at greater risk for dementia and cognitive impairment [1,2,3,4,5]
We found a significant increase in the relative surface area stained with factor VIII in the hippocampus of LDLr -/western diet (WD)-fed mice relative to both control wild type (WT) or LDLr -/- mice fed a control diet (CD), and in the thalamus compared to WT CD-fed mice (Fig 3A)
Since we found a significant increase in IBA1 staining in WT mice fed a WD, we attempted to determine the type of inflammatory response that was occurring
Summary
Previous studies have shown that elevated blood lipids and a diet high in saturated fats puts individuals at greater risk for dementia and cognitive impairment [1,2,3,4,5]. Low-density lipoprotein receptor null (LDLr -/-) mice are predisposed to elevated blood cholesterol levels and show evidence of cognitive impairment and increased brain inflammation when fed a high fat diet [9,10,11,12]. LDLr mediates the endocytosis of cholesterol rich low-density lipoproteins regulating plasma levels of cholesterol. It is prominently expressed in the liver, and the gastrointestinal tract, muscle (heart and skeletal) and brain [13]. Diet has been shown to activate microglia, resident brain inflammatory cells, and induce inflammation and cellular degeneration [8, 9, 19], each thought to contribute to the progression of cognitive impairment [20]
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