Non-Alcoholic Fatty Liver Disease, and the Underlying Altered Fatty Acid Metabolism, Reveals Brain Hypoperfusion and Contributes to the Cognitive Decline in APP/PS1 Mice.

Éric Thorin,Nilay Akkoyunlu,Caroline Daneault,Bernard I Levy,Anthony Pinçon,Philippe Pouliot,Olivia De Montgolfier,Frédéric Lesage,Nathalie Thorin-Trescases,Louis Villeneuve,Matthieu Ruiz

doi:10.3390/metabo9050104

Abstract

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfα, Cox2, p21, and Nox2, reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma β40- and β42-amyloid levels and altered hepatic but not brain expression of genes involved in β-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD.

Highlights

The brain is one of the most lipid-rich organs [1]
Since experimental data have shown that cerebral perfusion is decreased in patients with Alzheimer’s disease (AD) [34], and based on our observations of unchanged contralateral (Figure S1A in Supplementary Materials), ipsilateral (Figure S1B) and global brain perfusion (Figure S1C) in 6-month old amyloid precursor protein/presenilin-1 (APP/PS1) mice compared to wild-type (WT), fed with a standard diet, we aimed to evaluate whether lower brain perfusion in APP/PS1 mice may be revealed as a results of Non-alcoholic fatty liver disease (NAFLD) development
Weight gain in APP/PS1 mice fed a cholesterol-enriched diet (CHOL) diet for 18 weeks was lower than that measured in mice fed a standard diet (STD) diet despite similar food intakes between groups (Figure 1C,D)

Summary

Introduction

The brain is one of the most lipid-rich organs [1]. Cholesterol and fatty acids play a structural role in cell membranes and are involved in various biological functions. Brain cholesterol is essential for synaptogenesis [2], axonal growth [3], neurotransmitter release [4], and neuronal plasticity [5], while n-3 and n-6 polyunsaturated fatty acids (PUFAs) and their metabolites modulate inflammation [6,7,8], vasoreactivity [9], neurogenesis [10], brain glucose uptake [11,12], and cognition [6,7,13]. Clinical studies have shown that fatty acid and cholesterol levels are altered in the brains of Alzheimer’s disease (AD) patients [14,15,16,17].

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