Resistin protection against endogenous Aβ neuronal cytotoxicity from mitochondrial pathway

• Resistin could attenuate oxidative stress induced by endogenous Aβ.
• Resistin could improve mitochondrial dysfunction induced by endogenous Aβ.
• Resistin could inhibit mitochondrial apoptosis signal induced by endogenous Aβ.
• The protective effect of resistin in Aβ toxicity is independent on Aβ production.

Neurotoxicity of amyloid β (Aβ) plays an important role in Alzheimer's disease (AD) pathogenesis. In this study, we researched the potential protective effects of resistin against Aβ neurotoxicity in mouse Neuro2a (N2a) cells transfected with the Swedish amyloid precursor protein (Sw-APP) mutant and Presenilin exon 9 deletion mutant (N2a/D9), which overproduced Aβ with abnormal intracellular Aβ accumulation. The results show increased levels of ROS, NO, protein carbonyls, and 4HNE in N2a/D9 cells, which were attenuated by resistin treatment in a dose dependent manner. We also found that resistin could improve mitochondrial function in N2a/D9 cells through increasing the level of ATP and mitochondrial membrane potential. MTT and LDH assay indicated that N2a/D9 cells show increased vulnerability to H2O2-induced insult, which could be ameliorated by resistin. Mechanically, we found that resistin prevented apoptosis signals through reducing the ratio of Bax/Bcl2, the level of cleaved caspase-3, and attenuating cytochrome C release. Finally, the results demonstrated that resistin did not change the production of Aβ1–40 and Aβ1–42 in N2a/D9 cells, which suggests that the protective effects of resistin are independent of APP metabolism. This raises the possibility of novel AD therapies using resistin.