title: Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis.
abstract: The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD). Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis. Like in humans, apoE4 expression in animal models that develop Aβ amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression. However, whether decreasing levels of apoE3 or apoE4 would promote or attenuate Aβ-related pathology has not been directly addressed. To determine the effect of decreasing human apoE levels on Aβ accumulation in vivo, we generated human APOE isoform haploinsufficient mouse models by crossing APPPS1-21 mice with APOE isoform knock-in mice. By genetically manipulating APOE gene dosage, we demonstrate that decreasing human apoE levels, regardless of isoform status, results in significantly decreased amyloid plaque deposition and microglial activation. These differences in amyloid load between apoE3- and apoE4-expressing mice were not due to apoE4 protein being present at lower levels than apoE3. These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach.
authors.affiliation: Department of Neurology, Developmental Biology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Seonha
authors.initials: S
authors.lastname: Park
authors.forename: Adam E M
authors.initials: AE
authors.lastname: Eltorai
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Basak
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Finn
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020033:Protein Isoforms