Obesity in Aging Exacerbates Blood Brain Barrier Disruption and Neuroinflammation Leading to Synaptic Plasticity Deficit and Cognitive Decline in Mice

Abstract

There is growing evidence that obesity promotes vascular cognitive impairment in the elderly. Although obesity affects 38% of individuals aged 65 and older in the U.S., the specific microvascular mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced microvascular damage we compared young (7 mo) and aged (24 mo) control and high fat diet-fed obese C57BL/6 mice. We found that aging exacerbated obesity-induced blood brain barrier (BBB) disruption and neuroinflammation, as indicated by increased microglia activation, pro-inflammatory cytokine expression and oxidative stress. Obesity-induced neuroinflammation in aged mice was associated with impaired hippocampal-dependent cognitive function and reduced long-term potentiation (LTP) elicited by high frequency stimulation in hippocampal slices. Obesity-induced neuroinflammation in aged mice was associated with decline in hippocampal expression of several genes involved in learning, memory formation and LTP, including Grik1, Grik5, Gap43, Cask and Syngr1 (targeted qPCR array). Collectively, obesity-induced BBB disruption leads to a heightened state of neuroinflammation and significant synaptic plasticity deficit, which likely contribute to the significant cognitive decline observed in aged obese animals.