Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:42

Article

Soto, Ileana^1,2,3  Grabowska, Weronika A.^1,4  Onos, Kristen D.¹  Graham, Leah C.^1,5  Jackson, Harriet M.¹  Simeone, Stephen N.¹  Howell, Gareth R.^1,5 

[1] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[2] Rowan Univ, Dept Biol Sci, Glassboro, NJ USA

[3] Rowan Univ, Dept Biomed & Translat Sci, Glassboro, NJ USA

[4] Coll Atlantic, Bar Harbor, ME USA

[5] Tufts Univ, Sackler Sch Grad Biomed Sci, Grad Program Genet, Boston, MA 02111 USA

关键词: Neurovascular remodeling;    Neurodegeneration;    Aging;    Neurovascular deficits;   

DOI  :  10.1016/j.neurobiolaging.2016.02.025

来源: Elsevier

【 摘 要 】

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-beta (A beta) peptide is central to AD; however, evidence in humans and animals suggests that A beta 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 A beta 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. (C) 2016 The Authors. Published by Elsevier Inc.

【 授权许可】

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