Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model

Abstract

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer’s disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD.MethodsWT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months.ResultsDuring acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load.ConclusionsOur findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0467-5) contains supplementary material, which is available to authorized users.

Protective Effect of Genistein against Neuronal Degeneration in ApoE−/− Mice Fed a High-Fat Diet

“…ApoE deficiency significantly induced oxidative stress and inflammation in the hippocampus and cortex based on mRNA levels of related genes. Our previous analyses demonstrated that serum cholesterol levels are significantly correlated with systemic inflammation [18], which has a significant effect on the induction of neurodegeneration [4,38]. Therefore, in addition to increased expression of cytokines in the brain per se, systemic inflammation observed in hypercholesterolemic mice would aggravate the neuroinflammation in the brain.…”

Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury

“…A T-cut spinal cord hemisection injury was performed as previously described (Boato et al., 2010, Dooley et al., 2016, Geurts et al., 2015, Nelissen et al., 2013, Vangansewinkel et al., 2016, Vidal et al., 2013). See Supplemental Experimental Procedures for further details.…”

“…Spinal cord cryosections (10 μm) were obtained from animals transcardially perfused 4 weeks post injury with Ringer solution containing heparin, followed by 4% paraformaldehyde in 0.1 M PBS, and immunofluorescence analysis was performed as previously described (Boato et al., 2010, Dooley et al., 2016, Geurts et al., 2015, Nelissen et al., 2013, Vangansewinkel et al., 2016). See Supplemental Experimental Procedures for further details.…”

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Presence of OTRs on human immune cells suggests that OT plays a role in the neuroendocrine regulation of immunity with mainly anti-inflammatory effects (Wang et al, 2015). For example, administration of OT significantly attenuates lipopolysaccharide-induced production of pro-inflammatory cytokines tumor necrosis factor alpha ( TNF-α) and interleukin 6 ( IL-6) in serum of healthy human subjects (Clodi et al, 2008) and microglial production of TNF-α and interleukin 1 beta (IL-1β) in mice (Yuan et al, 2016). Considering its anti-inflammatory effects and growing evidence that inflammatory cytokines are involved in the etiology of MDD and PPD, it can be hypothesized that insufficient OT signaling may contribute to depression risk via this pathway (McQuaid et al, 2014).…”