P1-215: Rivastigmine promotes APP processing via α-secretase pathway: Studies from neuron culture and animal model to postmortem brain tissues and its implications in Alzheimer's disease (AD)

Alzheimer's disease (AD) is characterized by deposition of Aβ plaques and neuroinflammation leading to neuronal loss. Aβ is generated by enzymatic cleavage of amyloid precursor protein (APP) by β and γ secretase enzymes. APP is also processed by non-amyloidogenic ± -secretase, which precludes Aβ production. We have previously demonstrated that some cholinesterase inhibitors (ChEIs) alter APP processing (Lahiri et al., JPET, 2007). In this context, we report that rivastigmine, a ChEI used for mild-moderate AD also modulates APP processing in neuron culture, animal model and human subjects. We have treated primary human neurons with 100nM, 1 μM and 10 μM rivastigmine ± TAPI 2 for 4 days. APP transgenic mice were treated with rivastigmine for three weeks and postmortem brain bank tissues of AD patients who received only rivastigmine, non-medicated AD patients, and non AD controls were also analyzed Analyses of conditioned media (CM) samples from neuron culture showed a significant dose-dependent increase in levels of sAPP ± with rivastigmine treatments versus vehicle-treated samples. Furthermore, both Aβ (1-40) and (1-42) species and sAPPβ were significantly decreased by rivastigmine treatments. Analyses of intracellular proteins revealed a significant increase in levels of intracellular ADAM10, which is an ± -secreatse by all the doses of rivastigmine versus controls. We also observed increased sAPP ± and decreased soluble Aβ in the brains of Tg mice treated with rivastigmine versus controls. Analyses of postmortem brain samples revealed an increasing trend in the levels of brain sAPP ± in subjects who had received rivastigmine versus non-medicated subjects. Aβ (1-42) was also significantly decreased in the brain of rivastigmine-treated patients Increase sAPP ± , decreased sAPPβ and Aβ peptides by rivastigmine treatments indicate a shift in APP processing towards the ± -secreatse pathway, which was blocked by co-treatment of a non-selective ADAM inhibitor, TAPI2. This effect of rivastigmine was translated to animal model as well as in human subjects. Taken together, these results suggest that rivastigmine promotes the ± -secretase pathway by up-regulating or preserving ADAM10. Rivastigmine's dual functions, anticholinesterase and Aβ lowering properties, warrant further investigation in larger clinical settings.