Neuroinflammation and Cognitive Impairment in the Aged: Implications for Nutritional Intervention

128 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.Aged mice exhibit a heightened central inflammatory cytokine response, as well as prolonged hippocampal-dependent cognitive deficits, compared to adults when administered lipopolysaccharide (LPS) to mimic a peripheral infection. The excessive production of inflammatory cytokines such as interleukin (IL)-1beta within the brain is proposed to underlie acute cognitive disorders in elderly individuals with a viral or bacterial infection. In initial studies behavioral deficits in aged mice were exaggerated after either peripheral administration of LPS or intracerebroventricular (icv) administration of the HIV-1 viral envelope protein, gp120. In addition, pretreatment with IL-1 receptor antagonist (IL-1ra) icv attenuated the behavioral deficits and reduced hippocampal and hypothalamic IL-1beta levels in aged mice after peripheral injection of LPS. Recently, supplementing diets with a fruit or vegetable (e.g., blueberry, strawberry, spinach) has been shown to slow and even reverse age-related deficits in brain function, motor performance, and learning and memory. Considerable evidence suggests resveratrol, a polyphenol found in red grapes, elicits potent anti-inflammatory effects in the peripheral immune system, including inhibition of inflammatory mediators by stimulated monocytes and macrophages. Although resveratrol has been shown to inhibit peripheral inflammation, its effects on the inflammatory response in the brain are unknown. If resveratrol reduces inflammation in the brain, it is reasonable to hypothesize it will protect older animals from infection-related cognitive deficits. In a series of studies testing this hypothesis, resveratrol was found to inhibit LPS-induced IL-1beta production by BV-2 microglial cells in vitro. In another study, adult and aged mice were provided control or resveratrol-supplemented diet for four weeks and then injected i.p. with saline or LPS. As anticipated, deficits in locomotor activity and spatial working memory indicated aged mice are more sensitive to LPS compared to adults. More importantly, the LPS-induced deficits in aged animals were mitigated by dietary supplementation of resveratrol. Resveratrol consumption reduced LPS-induced IL-1beta in plasma 24h after injection. Furthermore, resveratrol attenuated the induction of hippocampal IL-1beta mRNA expression by LPS in aged mice. These data show that aged mice are more sensitive to both the inflammatory and cognitive effects of peripheral immune stimulation than are adult mice and suggest a possible role for resveratrol in attenuating acute cognitive disorders in elderly individuals with an infection.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD