The pathological mechanism of Alzheimer's disease (AD) needs to be elucidated. The Bcl-2 associated athanogene 5 (Bag5) is an important member in the Bag family. However, the role of Bag5 in AD has not yet been elucidated. In this study, we found that expression of Bag5 is elevated in the brains of AD transgenic Tg2576 mice at both mRNA levels and proteins. In vitro experiments indicated that Aβ1-42 treatment led to the upregulation of Bag5 in a dose-dependent manner. In addition, our results indicated that inhibition of Bag5 using small RNA interferences exacerbated Aβ1-42-induced neurotoxicity. On one hand, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay demonstrated that inhibition of Bag5 exacerbated Aβ1-42-related cell death. On the other hand, silence of endogenous Bag5 promotes the generation of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by Aβ1-42. Finally and importantly, it was shown that knockdown of Bag5 exacerbated Aβ1-42-induced apoptosis and caspase-3 cleavage. These data suggest that induction of Bag5 might have a neuroprotective effect in AD.