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Obesity in the western world has reached epidemic proportions, and yet the long-term effects on brain health are not well understood. To address this, we performed transcriptional profiling of brain regions from a mouse model of western diet (WD)-induced obesity. Both the cortex and hippocampus from C57BL/6J (B6) mice fed either a WD or a control diet from 2 months of age to 12 months of age (equivalent to midlife in a human population) were profiled. Gene set enrichment analyses predicted that genes involved in myelin generation, inflammation, and cerebrovascular health were differentially expressed in brains from WD-fed compared to control diet-fed mice. White matter damage and cerebrovascular decline were evident in brains from WD-fed mice using immunofluorescence and electron microscopy. At the cellular level, the WD caused an increase in the numbers of oligodendrocytes and myeloid cells suggesting that a WD is perturbing myelin turnover. Encouragingly, cerebrovascular damage and white matter damage were prevented by exercising WD-fed mice despite mice still gaining a significant amount of weight. Collectively, these data show that chronic consumption of a WD in B6 mice causes obesity, neuroinflammation, and cerebrovascular and white matter damage, but these potentially damaging effects can be prevented by modifiable risk factors such as exercise. • White matter damage is present in both humans and mouse models of obesity. • Myeloid cells increase in white matter regions in western diet (WD)-fed obese mice. • Blood-brain barrier dysfunction occurs in WD-fed obese mice. • Voluntary running prevented damaging effects of a WD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]