Alzheimer's disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid- (A) and neuroinflammation which promote the development of AD. Geniposide, the main ingredient isolated from Chinese herbal medicine Gardenia jasminoides Ellis, has a variety of pharmacological functions such as anti-apoptosis and anti-inflammatory activity. Hence, we estimated the inflammatory cytotoxicity caused by A(25-35) and the neuroprotective effects of geniposide in HT22 cells. In this research, following incubation with A(25-35) (40 M, 24 h) in HT22 cells, the methylthiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assays showed that the cell survival rate was significantly decreased. In contrast, the reactive oxygen species (ROS) assay indicated that A(25-35) enhanced ROS accumulation and apoptosis showed in both hoechst 33342 staining and annexin V-FITC/PI double staining. And then, immunofluorescence test revealed that A(25-35) promoted p65 to transfer into the nucleus indicating p65 was activated by A(25-35). Moreover, western blot analysis proved that A(25-35) increased the expression of nitric oxide species (iNOS), tumor necrosis factor- (TNF-), cyclooxygenase-2 (COX-2) and interleukin-1 (IL-1). Simultaneously, A(25-35) also promoted the expression of toll-like receptor 4 (TLR4), p-p65 and p-IB- accompanied with the increase in the level of beta-secretase 1 (BACE1) and caspase-3 which further supported A(25-35) induced apoptosis and inflammation. Fortunately, this up-regulation was reversed by geniposide. In conclusion, our data suggest that geniposide can alleviate A(25-35)-induced inflammatory response to protect neurons, which is possibly involved with the inhibition of the TLR4/NF-B pathway in HT22 cells. Geniposide may be the latent treatment for AD induced by neuroinflammation and apoptosis.