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.