P1‐216: Preclinical testing of lenalidomide as anti‐amyloid treatment for Alzheimer's disease

Abstract

Background: Alzheimer’s disease (AD) is characterized by deposition of Ab plaques and neuroinflammation leading to neuronal loss. Ab is generated by enzymatic cleavage of amyloid precursor protein (APP) by b and g secretase enzymes. APP is also processed by non-amyloidogenic6 -secretase, which precludes Ab 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.Methods:We have treated primary human neurons with 100nM, 1 mM and 10 mM rivastigmine6 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 Results: Analyses of conditioned media (CM) samples from neuron culture showed a significant dose-dependent increase in levels of sAPP 6 with rivastigmine treatments versus vehicle-treated samples. Furthermore, both Ab (1-40) and (1-42) species and sAPPb were significantly decreased by rivastigmine treatments. Analyses of intracellular proteins revealed a significant increase in levels of intracellular ADAM10, which is an6 -secreatse by all the doses of rivastigmine versus controls. We also observed increased sAPP6 and decreased soluble Ab 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 sAPP6 in subjects who had received rivastigmine versus non-medicated subjects. Ab (1-42) was also significantly decreased in the brain of rivastigmine-treated patientsConclusions: Increase sAPP6 , decreased sAPPb and Ab peptides by rivastigmine treatments indicate a shift in APP processing towards the6 -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 6 -secretase pathway by up-regulating or preserving ADAM10. Rivastigmine’s dual functions, anticholinesterase and Ab lowering properties, warrant further investigation in larger clinical settings.