Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system

Abstract

Acute cognitive disorders are common in elderly patients with peripheral infections but it is not clear why. Here we injected old and young mice with Escherichia coli lipopolysaccharide (LPS) to mimic an acute peripheral infection and separated the hippocampal neuronal cell layers from the surrounding hippocampal tissue by laser capture microdissection and measured mRNA for several inflammatory cytokines (IL-1β, IL-6, and TNFα) that are known to disrupt cognition. The results showed that old mice had an increased inflammatory response in the hippocampus after LPS compared to younger cohorts. Immunohistochemistry further showed more microglial cells in the hippocampus of old mice compared to young adults, and that more IL-1β-positive cells were present in the dentate gyrus and in the CA1, CA2 and CA3 regions of LPS-treated old mice compared to young adults. In a test of cognition that required animals to effectively integrate new information with a preexisting schema to complete a spatial task, we found that hippocampal processing is more easily disrupted in old animals than in younger ones when the peripheral innate immune system is stimulated. Collectively, the results suggest that aging can facilitate neurobehavioral complications associated with peripheral infections probably by allowing the over expression of inflammatory cytokines in brain areas that mediate cognitive processing.

SIGIRR modulates the inflammatory response in the brain

“…We report that SIGIRR -/-mice have increased expression of the microglial markers CD40 and ICAM in response to LPS compared to wildtype mice; the co-stimulatory molecules CD80 and CD86 were also upregulated SIGIRR -/-mice in response to LPS and this effect was not observed in wildtype mice. As previously reported, LPS increased IL-6 and TNFα at mRNA and protein levels in hippocampus (Chen et al, 2008;Hellstrom et al, 2005;Loane et al, 2007;Sparkman et al, 2006); significantly, and in parallel with the changes in vitro, the effect of LPS was markedly greater in hippocampus of SIGIRR -/-mice.…”

Active Immunization with Amyloid-β 1–42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

“…In fact, deficits in visuospatial tasks are reported in mice injected with LPS. After LPS treatment, mice show impaired performance in tests of cognition that require effective integration of new information to complete a spatial task (29). A further study in mice provides evidence for hippocampusdependent learning and memory impairment after LPS injection (30).…”

A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia

“…In animals, a number of studies have assessed the relationship between inflammation and cognitive performance in aged and younger adult mice, after an immune response evoked by peripheral infusion of lipopolysaccharide. After lipopolysaccharide administration, aged mice show an increased number of active microglial cells, and increased numbers of interleukin1b-positive microglial cells in the hippocampus, and a corresponding greater decline in working memory [95]. Findings in other studies that compared aged with younger adult mice include an increase in both proinflammatory and anti-inflammatory cytokines [96], a prolonged and exaggerated elevation in the brain inflammatory cytokines and oxidative stress, with subsequent more pronounced sickness behaviour [97], and prolonged depressive-like behaviour linked to a higher turnover rate of brain serotonin [98].…”