Blocking the A β1 42 RAGE interactions with a neutralizing antibody against RAGE confirmed that RAGE mediates the A β-induced decrease of P-gp expression, as bEnd.3 cell treated with A β1 42 in the presence of anti-RAGE antibody showed attenuation.
Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates A β-induced neurotoxicity.
Hence, our data indicate that glutamate binding to NMDARs rather than Ca2+ flux mediates A β-induced dendritic spine loss.
Consistent with this observation, we also showed that RanBP9 induces neurodegeneration in vivo and mediates A β-induced toxicity.
Upregulation of RAGE mediates A β-induced oxidative stress, activation of nuclear factor-κB, neuronal expression of macrophage colony-stimulating factor, and cell death.
Most significantly, we discovered that DR6 forms a receptor complex with p75NTR that mediates A β-induced neurotoxicity in cortical neurons.
Because A β is known to accelerate ROS generation by activating NADPH oxidase, and A β-induced Crif1 reduction is mediated by ROS, we examined whether NADPH oxidase mediates A β-induced Crfi1 regulation.
In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates A β-induced translocation of cofilin to mitochondria and induction of cofilin actin pathology in cultured cells, primary neurons, and in vivo.
These data suggest that GSK-3 may mediate the A β-AGE-induced exacerbation of neural impairments.
