Contributing Factor To Cerebral Inflammation And Correlations Between Cerebral Inflammation And Cognitive Impairment In A Transgenic Mouse Model Of Alzheimer's Disease

Backgroud and objective:Alzheimer's disease (AD) is a neurodegenerative disease of central nervous system, characterized by progressive memory loss, cognitive dysfunction and personality change. Although the aetiology and pathogenesis of AD are complex and largely unclear yet, it is believed that amyloid-beta protein (Aβ) aggregation, amyloid plaque formation and its neurotoxicity are an important pathological foundation for the onset and development of AD. It has been suggested that Aβ-mediated cerebral inflammation are invovled in the pathological process of AD and may play an important roal in the pathogenesis of AD. However, the contributing factor to cerebral inflammation and the correlations between cerebral inflammation and cognitive dysfunction in AD remain certain so far. To determine the contributing factor to the development of cerebral inflammation and its important role in the onset and development of AD, in the present study, we examined the changes of learning and memory ability and cerebral inflammation in 3-month-old APP/PS1 mice (before amyloid plaques formation) and in 12-month-old APP/PS1 mice (after amyloid plaques deposition).Methods:3- and 12-month-old APP/PS1 mice and age-matched wild-type littermates (WT) were used in this study. The spatial learning and memory abilities of all these mice were assessed by Morris water maze test. The changes of amyloid plaques and inflammatory cells in the brains of all mice were investigated by immunohistochemistry, and the changes of inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) in the brains of all mice were measured by ELISA. Furthermore, the correlations between the inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) in brains of APP/PS1 mice and their learning and memory performances were respectively examined.Results:1. In the brain of 3-month-old APP/PS1 mice, amyloid plaques and reactive astrocytes as well as activated microglial cells were not detected. There were no significant differences in the contents of inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) between 3-month-old APP/PS1 and WT mice (P > 0.05, respectively).2. Robust amyloid plaques accompanied by abundant activated astrocytes and microglia were clearly detected in the 12-month-old APP/PS1 mice. The contents of inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) were significantly elevated in the 12-month-old APP/PS1 mice compared to the 3-month-old APP/PS1 mice and 12-month-old WT mice (P < 0.05, respectively).3. No significant difference in the spatial learning was observed between the 3-month-old APP/PS1 mice and WT mice (P > 0.05), while the spatial memory was significantly declined in the APP/PS1 mice compared to the WT mice (P < 0.05). Correlation analysis disclosed no significant correlations between the declined spatial memory and the levels of inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) in the 3-month-old APP/PS1 mice (P > 0.05). (4) The spatial learning and memory were significantly impaired in the 12-month-old APP/PS1 mice compared to the WT mice (P < 0.05, respectively). Correlation analysis showed that the declined spatial learing and memory in the 12-month-old APP/PS1 mice was all significantly correlated with the levels of inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) (P < 0.05, respectively).Conclusions:1. Before the appearance of amyloid plaques, no particularly striking cerebral inflammation was observed in the 3-month-old APP/PS1 mice. Wheras after amyloid plaque deposition, the remarkable cerebral inflammation was noted in the 12-month-old APP/PS1 mice. These data suggest that the induction of cerebral inflammation is tightly associated with amyloid plaque formation, and deposition of amyloid-beta protein may be the direct contributing factor to the development of cerebral inflammation in AD.2. Before the formation of amyloid plaques, 3-month-old APP/PS1 mice exhibited the spatial memory impairment, but there was no significantly elevated cerebral inflammation in brains and also no significant relationship between the inflammatory factors (IL-1β, IL-6, TNFα, and PGE2) and the impaired spatial memory. These findings suggest that cerebral inflammation has no direct effect on the early memory impairment in AD.3. After amyloid plaque deposition, cerebral inflammation in the brain of 12-month-old APP/PS1 mice was significantly increased, and highly associated with the impaired spatial learning and memory. These data show that cerebral inflammation plays an important role in the progression of learing and memory impairment of AD. Taken together, these results indicate that the induction of cerebral inflammation may be provoked by Aβdeposition, and play an important role in the progression of AD.