We examined the mechanism by which lithium chloride (LiCl) attenuates the impaired learning and memory of APP/PS1 double transgenic (APP/PS1) mice.
Six- or twelve-month-old APP/PS1 and wild-type (WT) mice were divided randomly into 4 groups: WT, WT+Li (100 mg LiCl/kg body weight, gavage once daily), APP/PS1 and APP/PS1+Li. Primary rat hippocampal neurons were exposed to β-amyloid peptide oligomers (AβOs), LiCl and/or XAV939 (inhibitor of Wnt/β-catenin) or transfected with small interfering RNA against the β-catenin gene. Phosphor-glycogen synthase kinase-3β (GSK3β) (ser9), total GSK3β, β-catenin, cyclin D1, and α7 nAChR protein and mRNA were quantified by Western blotting or real-time PCR, respectively; senile plaques and α7 protein by immunohistochemical or immunofluorescent staining; Aβ 42 by ELISA; and cell viability by CCK8. Learning and memory were assessed utilizing the Morris water maze test.
In the brains of APP/PS1 mice, the level of Aβ was increased and those of α7 nAChR, phosphor-GSK3β (ser9), β-catenin, and cyclin D1 (at the protein and/or mRNA level) reduced. Treatment with LiCl for 2 months at 4 or 10 months of age attenuated all of these effects. Similar changes in the levels of these proteins were observed in primary neurons exposed to AβOs and these effects were attenuated by LiCl and aggravated by XAV939. Inhibition of β-catenin expression lowered the level of α7 nAChR protein in these cells.
LiCl attenuates the impaired ability of learning and memory of APP/PS1 mice via a mechanism that might involve elevation of the level of α7 nAChR as a result of altered Wnt/β-catenin signaling.