title: Genetic ablation of apolipoprotein A-IV accelerates Alzheimer's disease pathogenesis in a mouse model.
abstract: The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment.
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Cui
authors.forename: Mingwei
authors.initials: M
authors.lastname: Huang
authors.forename: Yingbo
authors.initials: Y
authors.lastname: He
authors.forename: Shuyan
authors.initials: S
authors.lastname: Zhang
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000209:etiology* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007859:Learning Disabilities / Q000150:complications / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016019:Survival Analysis
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001054:Apolipoproteins A; D053764:Presenilin-1; C022205:apolipoprotein A-IV