Obesity in Aging Exacerbates Blood-Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimer's Disease

Abstract

There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…On the one hand, 4 months of western diet given to 3 and 12 months APPswe/PS1 mice did not compromise BBB integrity (Theriault, ElAli, & Rivest, 2016). However, in another study, HFD‐induced obesity was shown to exacerbate BBB permeability in aged mice (24 months) measured by IgG extravagated to the hippocampus (Tucsek et al, 2014). The percentage of saturated fat in the diet of the latter study was the same as in our study.…”

“…In others, obesity exacerbated early postischemic BBB disruption in 16‐week‐old mice fed HFD. Tucsek et al (2014) showed that 7 months of HFD did not change the BBB permeability (measured by IgG levels) in the hippocampus, but an exacerbated damage of the BBB was found at 24 months with HFD. The impact of HFD on memory and cognition is also controversial and depends on the composition of the fat and the time of exposure to HFD.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…Immunofluorescent labeling for CD31 was used to identify microvessels in the brain as we previously described (Toth et al 2013a;Tucsek et al 2014;Warrington et al 2011). Capillary density in the CA1 region of the hippocampus was quantified, using stereological methods, as the length of blood vessels <10 μm in diameter per volume of tissue using Neurolucida with AutoNeuron (MicroBrightField, Williston, VT).…”

“…Targeted qPCRarray to analyze mRNA expression of pro-and anti-angiogenic factors A quantitative real time RT-PCR technique was used to analyze mRNA expression of genes known to be involved in regulation of angiogenesis and microvascular regression in hippocampi of mice from each experimental group as reported (Toth et al 2013a;Tucsek et al 2003;Tucsek et al 2014;Csiszar et al 2013). In brief, total RNA was isolated with a Mini RNA Isolation Kit (Zymo Research, Orange, CA) and was reverse transcribed using Superscript III RT (Invitrogen) as described previously (Bailey-Downs et al 2012a).…”

“…There is growing evidence that alterations of the cerebral microcirculation play a key role in age-related decline in higher brain function (Toth et al 2013a;Tucsek et al 2003;Tucsek et al 2014;Zlokovic 2011). Normal brain function is critically dependent on a continuous, tightlycontrolled supply of oxygen and nutrients through adequate cerebral blood flow.…”