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

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 alpha (DFFA) and cysteine aspartic acid protease-3 (caspase 3) via beta-amyloid protein (A beta)-depressing mechanisms. Moreover, the meloxicam treatment blocked the effects of beta-amyloid protein oligomers (A beta o) on stimulating the synthesis of tumor necrosis factor alpha (TNF-alpha) and TNF-like ligand 1A (TL1A) in neuroblastoma (N) 2a cells. TNF-alpha 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 A beta o on inducing neuronal apoptosis, which was corroborated by the efficacy of meloxicam in inhibiting A beta o-induced neuronal apoptosis. By ameliorating neuronal apoptosis, meloxicam improved memory loss in APP/PS1 Tg mice.