L1CAM mimetic compound duloxetine improves cognitive impairment in 5xFAD mice and protects Aβ1-42-damaged HT22 cells.

Background: Synapse loss and damage are underlying causes of Alzheimer's disease. Duloxetine has been identified as a mimetic of neural adhesion molecule L1CAM, a neuronal synapse component, suggesting duloxetine could be therapeutic for Alzheimer's disease.

Methods: Cognitive function in 5xFAD mice was evaluated by open field, novel object recognition, and Morris water maze tests. Hippocampal and cortical Aβ1-40, Aβ1-42 and amyloid plaque deposition were quantified by ELISA and immunohistochemistry. RT-qPCR and western blotting quantified the effects of duloxetine treatment on L1CAM levels and PI3K/Akt/CREB signaling pathway activation. Apoptosis markers Bcl-2 and Bax were also measured by RT-qPCR and western blotting. HT22 cell survival was measured by CCK8 assay.

Results: Duloxetine preserved learning and memory abilities, but had no effect on locomotor performance of 5xFAD mice. Duloxetine decreased Aβ1-42 expression levels, increased Aβ1-40 levels, reduced amyloid plaque formation, and activated the PI3K/Akt/CREB signaling pathway in both cortices and hippocampi of 5xFAD mice. Moreover, duloxetine increased the expression of L1CAM and Bcl-2, and inhibited the expression of Bax, as well as prevented Aβ1-42 cytotoxicity in wild-type, but not L1CAM-knockdown HT22 cells, suggesting a feed-forward mechanism for duloxetine-mediated neuroprotection, whereby duloxetine induces and activates L1CAM to exert neuroprotective effects.

Conclusions: Our findings demonstrate that duloxetine plays a neuroprotective role in 5xFAD mice and HT22 cells through activating L1CAM, likely by regulating the PI3K/Akt/CREB signaling pathway. These results suggest that duloxetine may be a potential reagent for the treatment of Alzheimer's disease.