Multiple Inflammatory Pathways Are Involved In The Development And Progression Of Cognitive Deficits In APPswe/PS1dD9mice

(Objective] Researches have revealed that increased deposition of amyloid-beta peptide (Aβ) and inflammatory reaction exist in the brains of patients with Alzheimer’s disease (AD). However, it remains unclear which pathological form of Aβ triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. On the basis of previous studies, this research try to further discuss the relationship between different pathological forms of Aβ and neuroinflammation, as well as relationship between neuroinflammation and cognitive decline in AD. Our present study may be helpful to provide novel strategy for prevention and treatment of AD.[Methods] The3.5,6, and12months APPswe/PS1dE9mice and their age-matched wild type (WT) littermates were used in this study (n=7, per group). Abilities of acquired spatial learning and spatial memory were estimated by Morris water maze test. Total Aβ plaque load, fibrillar Aβ plaque load, activated astrocytes and microglia were detected by immunohistochemistry and fluorescence staining. The levels of soluble Aβ, insoluble Aβ, IL-1β, IL-6, TNFa and PGE2in the samples were determined by ELISA method. Based on these results, the correlation ships between different pathological forms of Aβ and neuroinflammation, as well as the correlationships between neuroinflammation and cognitive deficits in APPswe/PS1dE9mice were discussed by correlative analysis method.[Results](1) In Morris water maze test, there was no significant difference in escape latency over all training days between3.5-month APPswe/PS1dE9mice and WT mice, and the escape latencies were significantly longer in6-month and12-month APPswe/PS1dE9mice compared with matched WT mice.(2) In immunohistochemical and fluorescence staining analysis, there was no detectable Aβ deposit in3.5-month APPswe/PS1dE9mice, but compared with6-month APPswe/PS1dE9mice, the number of total Aβ plaques and fibrillar Aβ plaques were significantly increased in12-month APPswe/PS1dE9mice. In ELISA analysis, there were significant differences in the level of soluble Aβ among the groups of APPswe/PS1dE9mice. Insoluble Aβ was not detected in3.5-month APPswe/PS1dE9mice, but compared with6-month APPswe/PS1dE9mice, the level of insoluble Aβ was significantly increased in12-month APPswe/PS1dE9mice.(3) In immunohistochemical analysis, there was no significant difference in the number of actived astrocytes between3.5-month APPswe/PS1dE9mice and WT mice, but compared with matched WT mice, the number of actived astrocytes was significantly increased in6-month and12-month APPswe/PS1dE9mice respectively, and there were significant differences in the number of actived microglial cells among the groups of APPswe/PS1dE9mice. In ELISA analysis, compared with matched WT mice, levels of IL-1β, IL-6, TNFa and PGE2were greatly increased in different groups of APPswe/PS1dE9mice respectively, and there were also significant differences in the levels of IL-1β, IL-6, TNFa and PGE2among the groups of APPswe/PS1dE9mice.(4) In correlative analysis, the level of soluble Aβ was positively correlated with the number of activated gliocytes, the levels of IL-1β, IL-6, TNFa and PGE2in different age groups of APPswe/PS1dE9mice. However, there was no significant correlationship between these inflammatory reaction indicators and total Aβ plaque, fibrillar Aβ plaque or insoluble Aβ.(5) In correlative analysis, the ability of spatial memory in3.5-month APPswe/PS1dE9 mice was negatively correlated with the number of activated microglial cells, the levels of IL-1β, IL-6, TNFa and PGE2, and the abilities of spatial learning and spatial memory in6-month and12-month APPswe/PS1dE9mice were negatively correlated with the number of activated gliocytes, the levels of IL-1β, IL-6, TNFa and PGE2.[Conclusion](1) Inflammatory reaction may be enhanced in the early pre-plaque stage of AD, and significantly increased in both early-plaque and late-plaque stages in APPswe/PS1dE9mice.(2) Multiple inflammatory indicators were shown to be closely correlated with level of soluble Aβ, rather than that of Aβ plaque or insoluble Aβ in APPswe/PS1dE9mice.(3) Moreover, multiple inflammatory indicators were shown to be highly correlated with the impaired ability of spatial learning and memory in APPswe/PS1dE9mice. Collectively, these results provide evidence that inflammatory reaction in AD might be triggered by soluble Aβ, and multiple inflammatory pathways might be involved in the occurence and progression of cognitive deficits in AD, suggesting a novel pharmacological approach against multiple inflammatory pathways for prevention and treatment of AD.