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

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

  • Eur J Pharmacol. 2025 Mar 6:997:177476. doi: 10.1016/j.ejphar.2025.177476.
Hanyu Chen 1,  Zhou Fang 1,  Stanley Li Lin 2,  Melitta Schachner 3
Affiliations

Affiliations

  • 1 Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, 515041, China.
  • 2 Shantou Key Laboratory of Precision Diagnosis and Treatment of Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, China; Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, China. Electronic address: stanleylin@stu.edu.cn.
  • 3 Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, 515041, China; Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ, 08554, USA. Electronic address: schachner@dls.rutgers.edu.
PMID: 40057157 DOI: 10.1016/j.ejphar.2025.177476
Abstract

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.

Keywords

Alzheimer's disease; Bax; CREB; PI3-Kinase.

Figures
Products