Correlations Between Different Forms Of Aβ And Cognitive Deficits In Appswe/ps1de9 Mice

Background and objective:Alzheimer's disease (AD) is the most common form of dementia. Due to the deficiency of specific measures for AD prevention and treatment, it has become one of the most important diseases, which shows great danger to physical and mental health for elderly people. AD is a degenerative disease of central nervous system, characterized by progressive cognitive deficits as main clinical symptoms. Although the exact etiology and pathogenesis of AD have not been fully clarified, current evidence indicates that the amyloid-beta protein (Aβ) and its aggregation as well as deposits and its neurotoxicity are important pathological basis for the development of AD. Many pathological Aβforms (i.e., insoluble Aβ, soluble Aβ, diffuse plaques, and insoluble plaques) exist in the brain of AD patients. However, which form(s) of Aβpathology is closely related to the onset and progression of cognitive deficits in AD remains uncertain. Therefore, a further better understanding on the pathogenesis of AD cognitive deficits will benefit for the new therapeutics against dementia. The present study aimed to investigate the determinants of the cognitive deficits in APPswe/PS1dE9 transgenic mice. Methods: The 12-month-old APPswe/PS1dE9 mice and their matched non-transgenic wild-type littermates were used in this study. A standard Morris water maze task was used to assess the spatial learning and memory,, and the step-down type passive avoidance test was used to assess the long-term contextual memory. The Aβpathologies were measured from hippocampal and cortical tissues by ELISA assay, immunohistochemical and histological staining. Correlations and multiple regression analysis were performed to investigate the determinants of the cognitive deficits in transgenic mice.Results: The water maze test showed that the escape latencies in APPswe/PS1dE9 mice were significantly longer relative to WT mice (P < 0.001), indicating that spatial learning was impaired in these transgenic mice; APPswe/PS1dE9 mice spent lower time in the target quadrant than WT mice (P < 0.001), indicating impaired spatial memory retention in these transgenic mice. The step-down latency of APPswe/PS1dE9 mice was significantly lower than that of WT mice (P < 0.001), indicating impaired long-term contextual memory in these transgenic mice.Correlational analysis revealed that the spatial learning performances were positively correlated with the levels of hippocampal soluble Aβ1-40 (r = 0.972, P < 0.001) and Aβ1-42 (r = 0.991, P < 0.001); long-term contextual memory performances were inversely correlated with the levels of hippocampal soluble Aβ1-40 (r =– 0.939, P < 0.01) and Aβ1-42 (r =– 0.866, P < 0.01); spatial memory performances were inversely correlated with the levels of hippocampal soluble Aβ1-40 (r =– 0.848, P < 0.01) and Aβ1-42 (r =– 0.873, P < 0.01), as well as levels of cortical soluble Aβ1-40 (r =– 0.934, P < 0.01) and Aβ1-42 (r =– 0.955, P < 0.001). in contrast, there were no significant correlations between any other Aβmeasures (cortical and hippocampal total Aβ1-40 or Aβ1-42 levels, insoluble Aβ1-40 or Aβ1-42 levels, total Aβplaque burden, or fibrillar Aβplaque burden) and the cognitive variables (P > 0.05, respectively).Stepwise multiple regression analysis identified that hippocampal soluble Aβ1-40 and Aβ1-42 levels were the independent factors for predicting the spatial learning performances (R2 = 0.992, P < 0.001) and the long-term contextual memory performances (R2 = 0.882, P < 0.01), and hippocampal soluble Aβ1-40 and Aβ1-42 levels as well as cortical soluble Aβ1-40 and Aβ1-42 levels were the independent factors for predicting the spatial memory performances (R2 = 0.990, P < 0.01).Conclusion: These results in this study demonstrate that spatial learning and long-term contextual memory performances are highly related to the levels of soluble Aβ1-40and Aβ1-42 in APPswe/PS1dE9 mice, and spatial memory performances are inversely correlated with the levels of hippocampal soluble Aβ1-40 and Aβ1-42, as well as levels of cortical soluble Aβ1-40 and Aβ1-42. Our findings indicate that soluble Aβis the determinant to cognitive deficits in AD, and plays an important role in the progression of cognitive deficits in AD. Reducing the levels of soluble Aβspecies would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aβ.