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-3β. 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 Acet-tub significantly decreased in depressive-like rats, and
fluoxetine attenuated microtubule instability. Finally, the inhibition of CUMS-induced PI3K/Akt activated GSK-3β, 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 /GSK3β pathway in adult depressive-like rats, and hippocampal LRP1 might be involved in the development of depression.