title: Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease.
abstract: Evidence suggests that multiple genetic and environmental factors conspire together to increase susceptibility to Alzheimer's disease (AD). The amyloid cascade hypothesis states that deposition of the amyloid-β (Aβ) peptide is central to AD; however, evidence in humans and animals suggests that Aβ buildup alone is not sufficient to cause neuronal cell loss and cognitive decline. Mouse models that express high levels of mutant forms of amyloid precursor protein and/or cleaving enzymes deposit amyloid but do not show neuron loss. Therefore, a double-hit hypothesis for AD has been proposed whereby vascular dysfunction precedes and promotes Aβ toxicity. In support of this, copy number variations in mesenchyme homeobox 2 (MEOX2), a gene involved in vascular development, are associated with severe forms of AD. However, the role of MEOX2 in AD has not been studied. Here, we tested Meox2 haploinsufficiency in B6.APP/PS1 (B6.APB(Tg)) mice, a mouse model of AD. Despite no overt differences in plaque deposition or glial activation, B6.APB(Tg) mice that carry only one copy of Meox2 (B6.APB(Tg).Mx(-/+)) show increased neuronal cell loss, particularly in regions containing plaques, compared with B6.APB(Tg) mice. Neuronal cell loss corresponds with a significant decrease in plaque-associated microvessels, further supporting a synergistic effect of vascular compromise and amyloid deposition on neuronal cell dysfunction in AD.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA; Department of Biological Science, Rowan University, Glassboro, NJ, USA; Department of Biomedical and Translational Sciences, Rowan University, Glassboro, NJ, USA.
authors.forename: Ileana
authors.initials: I
authors.lastname: Soto
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA; College of the Atlantic, Bar Harbor, ME, USA.
authors.forename: Weronika A
authors.initials: WA
authors.lastname: Grabowska
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Onos
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA; Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Graham
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Jackson
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Simeone
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA; Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA. Electronic address: gareth.howell@jax.org.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Howell
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D057895:Haploinsufficiency / Q000235:genetics* / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D065852:Spatial Memory
chemical_list: D016229:Amyloid beta-Peptides; D018398:Homeodomain Proteins; C484194:Meox2 protein, mouse
keywords: Aging; Neurodegeneration; Neurovascular deficits; Neurovascular remodeling