P2‐254: Acute inhibition of gamma secretase lowers abeta dimer levels in plaque‐bearing PSAPP mice

pathology appears to be due to LC degeneration and not simply low NA levels. This suggests that NA potentiates Ab toxicity. Indeed, catecholamines potentiate Ab misfolding and oxidative toxicity. For example, catecholamines both undergo autooxidation and increase Ab oxidative stress. Dopamine, a catecholamine, increases Ab misfolding into toxic oligomeric amyloid forms and it is likely that other catecholamines have a similar effect. Currently, the mechanism of how catecholamines catalyze Abmisfolding and augment oxidative toxicity is unknown.Methods:We have studied the effects of the catecholamines, dopamine, noradrenaline and adrenaline on Ab misfolding and oxidative stress in vitro using mass spectrometry, western blots, electron microscopy, protease protections assays and cell culture. Results: Our data demonstrates that all catecholamines increase Ab misfolding (likely oligomers) in vitro. Preliminary protease protection assay experiments and electron microscopy suggest that Ab oligomers are formed upon incubation with catecholamines. Additionally, we demonstrate that this process is enhanced by addition of the transition metal Cu and inhibited by EDTA and the antioxidant BHT. Structurally related compounds incompetent for autooxidation do not cause Ab misfolding or oxidative stress. The extent of catecholamine oxidation will be ascertained via LC/ MS and adduct formation with Ab via MALDI. Additionally, the effect of catecholamines on oxidative toxicity in vitro and in cultured cells will be ascertained. Conclusions: Thus, we have evidence that catecholamine neurotransmitters catalyze Ab misfolding and augment its oxidative stress in vitro. Extrapolation from this data suggests that catecholamines could play a role in Ab pathogenesis in AD.