title: 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: BACKGROUND
  Non-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.
  
  
  METHODS
  WT 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.
  
  
  RESULTS
  During 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.
  
  
  CONCLUSIONS
  Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. dk594@cornell.edu.
authors.forename: Do-Geun
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. ak859@cornell.edu.
authors.forename: Antje
authors.initials: A
authors.lastname: Krenz
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. let39@cornell.edu.
authors.forename: Leon E
authors.initials: LE
authors.lastname: Toussaint
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. km429@cornell.edu.|Center for Animal Resources and Education, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. km429@cornell.edu.|Center for Comparative Medicine and Research, Dartmouth College, 1 Medical Center Drive, 302 W Borwell, Lebanon, NH 03756, USA. km429@cornell.edu.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Maurer
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. sr687@cornell.edu.
authors.forename: Sudie-Ann
authors.initials: SA
authors.lastname: Robinson
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. ay296@cornell.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. lft9@cornell.edu.
authors.forename: Luisa
authors.initials: L
authors.lastname: Torres
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. msb76@cornell.edu.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Bynoe
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005223:Fats / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020556:Neutrophil Infiltration; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000209:etiology; D058225:Plaque, Amyloid / Q000473:pathology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005223:Fats; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D051193:Toll-Like Receptors; D025521:Tumor Suppressor Proteins