Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele

Abstract

BackgroundNumerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia.MethodsAged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers.ResultsWe show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6.ConclusionsOur results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke.

Trans-sodium crocetinate provides neuroprotection against cerebral ischemia and reperfusion in obese mice

“…Therefore, reducing inflammatory responses in the ischemic brain tissues might be a mechanism for TSC‐induced neuroprotection. Consistent with this possibility, enhancing neuroinflammation after brain ischemia might contribute to the worsened neurological outcome in rodents with obesity (Tu et al, ; Dhungana et al, )…”

“…Hyperlipidemia has also been shown to increase stroke severity (Mikdashi et al, 2007), although opposite findings have been reported (Olsen et al, 2007;Jimenez-Conde et al, 2010). Obesity can induce neuroinflammation (Purkayastha and Cai, 2013;Buckman et al, 2014) and worsen neuroinflammation and neurological outcomes after brain ischemia (Tu et al, 2011;Dhungana et al, 2013). Neuroinflammation is a significant pathological process that leads to cell injury (Lipton, 1999;Li et al, 2013).…”

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

“…The temperature of the mice was controlled by a homeothermic control system connected to a heating blanket and rectal probe (Harvard apparatus; PanLab, Barcelona, Spain). The left middle cerebral artery (MCA) was permanently occluded as described (Dhungana et al, 2013b). Briefly, the temporal bone was first exposed and a 1-mm-diameter hole was drilled to expose the artery.…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…Nonetheless, how apoE status affects obesity-associated inflammation is unclear, as one study reported that apoE knockout mice show a stronger pro-inflammatory response in adipose tissue than wildtype mice (Pereira et al, 2012), whereas another study found that apoE knockout mice on HFD have lower levels of inflammatory cytokines in adipose tissue and skeletal muscle (Wang et al, 2012). Interestingly, apoE4 mice fed a HFD are more susceptible to motor deficits after stroke, and this is accompanied by increased inflammation (Dhungana et al, 2013). Overall, the literature demonstrates an interaction between apoE and obesity, but more research is needed to clarify how this relationship affects inflammation.…”