Involvement of chronic unpredictable mild stress-induced hippocampal LRP1 up-regulation in microtubule instability and depressive-like behavior in a depressive-like adult male rat model

Low-density lipoprotein receptor-related protein 1 (LRP1) and tau play an important role in developing Alzheimer's disease. This study aimed to explore the involvement of LRP1 in microtubule dynamic and depressive-like behavior in a depressive-like rat model. It also investigated whether fluoxetine blocked the change induced by chronic unpredictable mild stress (CUMS). Sprague-Dawley rats (200-250 g) were exposed to CUMS and fluoxetine for 4 weeks respectively. The body weight was determined, and behavior tests, including sucrose preference test, forced swimming test and open field test were performed. Western blot analysis was conducted to determine the protein levels of LRP1, tubulin, Acet-tub, Tyr-tub and PI3K/Akt/GSK-3 beta. Real-time quantitative polymerase chain reaction was used for mRNA expression levels of LRP1. Immunohistochemical staining was applied for LRP1 and immunofluorescence staining for the co-location of p-tau (404,262) and Acet-tub. The CUMS group presented a decreased body weight and depressive-like behavior, which was improved by fluoxetine. The protein and mRNA expression levels of LRP1 were elevated in the CUMS group. The levels of Acet-tub increased following CUMS, accompanied by elevated levels of p-tau (404,262). The binding of p-tau and Acettub significantly decreased in depressive-like rats, and fluoxetine attenuated microtubule instability. Finally, the inhibition of CUMS-induced PI3K/Akt activated GSK-3 beta, and fluoxetine reversed the change in the signaling pathway. Hence, LRP1 might impair the microtubule dynamics accompanied by depressive-like behavior via the PI3K/ Akt /GSK3 beta pathway in adult depressive-like rats, and hippocampal LRP1 might be involved in the development of depression.