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P1‐227: MITOCHONDRIAL MEMBRANE POTENTIAL INFLUENCE ON PROCESSING AND LOCALIZATION OF APP
Author(s) -
Wilkins Heather M.,
Weidling Ian,
Swerdlow Russell H.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.232
Subject(s) - oligomycin , depolarization , membrane potential , mitochondrion , bioenergetics , atp synthase , inner mitochondrial membrane , microbiology and biotechnology , biology , biophysics , biochemistry , chemistry , atpase , enzyme
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.