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 peptide is central to AD; however, evidence in humans and animals suggests that amyloid-β build-up 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 (APP) 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 amyloid-β 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 to 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.