P1‐227: MITOCHONDRIAL MEMBRANE POTENTIAL INFLUENCE ON PROCESSING AND LOCALIZATION OF APP

neuroblastoma cells and cell homogenates, and reversed the Abinduced increases in superoxide formation. KU-32 increased the Vmax of mitochondrial Complex I without affecting levels of Complex I proteins, and blocked the Ab inhibition of Complex I. We determined that the effects on Complex I were the result of inhibition of pyruvate dehydrogenase kinase (PDHK), both in isolated brain mitochondria and in SH-SY5Y cells. PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Ab-induced cell injury similarly to KU-32. Inhibition of PDHK would lead to activation of the PDH complex, increase acetyl-CoA generation, stimulate the tricarboxylic acid cycle and Complex I, and enhance oxidative phosphorylation. Bioenergetic measurements in SH-SY5Y showed increases in oxygen consumption rates in KU-32-treated cells. Conclusions:These studies point to the potential value of PDHK as a target in AD therapy.