Mitochondrial failure in a transgenic mice model of Alzheimer's disease with plaques and tangles

Alzheimer's disease is characterized by neuropathological hallmarks of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain of patients. Amyloid plaques are composed of the amyloid-beta (Aβ) protein, derived from its precursor protein APP. Neurofibrillary lesions are formed from paired helical filaments composed of hyperphosphorylated tau protein. Importantly, current data indicate a complex relation between the amyloid pathology and pathology involving microtubule-associated protein tau during disease. Based on our previous findings, we hypothesize a direct impact of abnormally phosphorylated tau and Aβ on proteins/enzymes involved in energy metabolism and mitochondrial respiratory chain. For this approach we are currently investigating the brains of double (APP (KM670/671NL)/PS2(N141l)) and triple (APP(KM670/671NL)/PS2(N141l)/Tau(P301L)) transgenic mice at the age of 7–8, 12 and 16 months. Mitochondrial respiration is studied by the measurement of oxygen consumption with substrates and inhibitors specific for the mitochondrial chain complexes I and IV. In addition, enzyme activities of these complexes will be determined. Our preliminary findings indicate that at the level of mitochondria, the two defining neuropathological AD proteins, tau and A?, seem to act in a synergistic or additive way finally leading to/accelerating neurodegenerative mechanisms and cell death. Supported by SNF grant 310000–108223 and Eli Lilly Int. Found. grant to AE