title: Identification and modification of amyloid-independent phenotypes of APOE4 mice.
abstract: Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (APOE4), but have no course for reducing their risk. The association of non-steroidal anti-inflammatory drug (NSAID) use with reduced risk of AD for APOE4-carriers suggests that NSAIDs may be useful in AD prevention.
  
  
  
  We identified phenotypes associated with APOE4 in APOE knock-in mice in order to define modifiable measures that correlate with risk of AD.
  
  
  
  APOE4 mouse brains showed altered post-translational modifications and biochemical distribution of APOE compared to APOE3 mice; these differences were also observed in brains of human APOE4 carriers. Two-month treatment with ibuprofen significantly altered the expression pattern of APOE in APOE4 mice to that of APOE3 mice; PPAR-γ agonist pioglitazone also had a significant effect. APOE4 mice also show deficits in dendritic spine density, and ibuprofen and pioglitazone significantly increased dendritic spine density.
  
  
  
  We report new phenotypes associated with APOE4 in human and APOE knock-in mice and their mitigation with NSAID treatment, through COX-2 inhibition and PPAR-γ activation.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: DiBattista
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Sonya B
authors.initials: SB
authors.lastname: Dumanis
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Newman
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA. Electronic address: gwr2@georgetown.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000068579:Celecoxib / Q000494:pharmacology / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D000077205:Pioglitazone; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053327:Apolipoprotein E4; D052246:Cyclooxygenase 2 Inhibitors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000068579:Celecoxib; D007052:Ibuprofen; D000077205:Pioglitazone
keywords: APOE; Celecoxib; Ibuprofen; NSAID; Pioglitazone; Preventative treatment