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Meloxicam Inhibits Apoptosis in Neurons by Deactivating Tumor Necrosis Factor Receptor Superfamily Member 25, Leading to the Decreased Cleavage of DNA Fragmentation Factor Subunit α in Alzheimer’s Disease

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Abstract  

Neuronal apoptosis is considered to be a critical cause of Alzheimer’s disease (AD). Recently, meloxicam has shown neuroprotective effects; however, the inherent mechanisms are highly overlooked. Using APP/PS1 transgenic (Tg) mice as in vivo animal models, we found that meloxicam inhibits apoptosis in neurons by deactivating tumor necrosis factor receptor superfamily member 25 (TNFRSF25), leading to the suppression of the expression of fas-associated protein with death domain (FADD) and the cleavage of DNA fragmentation factor subunit α (DFFA) and cysteine aspartic acid protease-3 (caspase 3) via β-amyloid protein (Aβ)-depressing mechanisms. Moreover, the meloxicam treatment blocked the effects of β-amyloid protein oligomers (Aβo) on stimulating the synthesis of tumor necrosis factor α (TNF-α) and TNF-like ligand 1A (TL1A) in neuroblastoma (N) 2a cells. TNF-α and TL1A induce apoptosis in neurons via TNFR- and TNFRSF25-dependent caspase 3-activating mechanisms, respectively. Knocking down the expression of TNFRSF25 blocked the effects of TL1A on inducing apoptosis in neurons by deactivating the signaling cascades of FADD, caspase 3, and DFFA. Consistently, TNFRSF25 shRNA blocked the effects of Aβo on inducing neuronal apoptosis, which was corroborated by the efficacy of meloxicam in inhibiting Aβo-induced neuronal apoptosis. By ameliorating neuronal apoptosis, meloxicam improved memory loss in APP/PS1 Tg mice.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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This work was supported, in part or in whole, by the National Natural Science Foundation of China (CN) (81870840).

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  1. Peipei Guan and Di Zhu contributed equally to this work.

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  1. College of Life and Health Sciences, Northeastern University, No. 3-11. Wenhua Road, Shenyang, 110819, People’s Republic of China

    Peipei Guan, Di Zhu & Pu Wang

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P.P.G. and D.Z. conceived and performed all of the experiments and participated in the design of the study. P.W. interpreted the data and wrote the manuscript of this study.

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Correspondence to Pu Wang.

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Guan, P., Zhu, D. & Wang, P. Meloxicam Inhibits Apoptosis in Neurons by Deactivating Tumor Necrosis Factor Receptor Superfamily Member 25, Leading to the Decreased Cleavage of DNA Fragmentation Factor Subunit α in Alzheimer’s Disease. Mol Neurobiol 60, 395–412 (2023). https://doi.org/10.1007/s12035-022-03091-z

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