期刊
NEUROBIOLOGY OF AGING
卷 42, 期 -, 页码 50-60出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.02.025
关键词
Neurovascular remodeling; Neurodegeneration; Aging; Neurovascular deficits
资金
- Jackson Laboratory Nathan Shock Center for Excellence in the Basic Biology of Aging
- Fraternal Order of the Eagle
- Jane B. Cook Foundation
- National Institutes of Health (NIH) [R01 EY021525]
- Institutional Development Award (IDeA) from National Institute of General Medical Sciences of the NIH [P20GM103423]
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.
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