Portal de Periódicos da CAPES

P2‐140: Mitochondrial failure in a transgenic mice model of Alzheimer's disease with plaques and tangles

2008; Wiley; Volume: 4; Issue: 4S_Part_12 Linguagem: Inglês

10.1016/j.jalz.2008.05.1213

1552-5279

Virginie Rhein, Ginette Baysang, Fides Meier, Laurence Ozmen, Hurs Bluethmann, Stefan Dröse, Ulrich Brandt, F. Müller‐Spahn, Christian Czech, Jurgen Goetz, Anne Eckert,

Mitochondrial Function and Pathology

Alzheimer's disease (AD) is the most frequent form of dementia among the elderly and is characterized by neuropathological hallmarks of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain of AD 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, a microtubule-associated-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)), triple (APP (KM670/671NL)/PS2 (N141l)/Tau (P301L) and single Tau (P301L) transgenic mice at the age of 2, 4, 7–8, 12 and 16 months. Proteomics studies are combined with functional analysis of mitochondria. Mitochondrial respiration is studied with a high-resolution respirometry system (Oxygraph-2k). In addition, enzyme activities of complexes I and IV will be determined with spectrophotometric and colorimetric assays. ROS levels, mitochondria membrane potential and ATP levels are determined in cortical brain cells from the mice using fluorescence and bioluminescence assays. We have first ex vivo evidence of relationship between Aβ and/or tau pathologies and alterations of mitochondrial function. Indeed, in triple transgenic mice mitochondrial function is reduced compared to double transgenic mice and to single transgenic tau mice. In fact, activities of mitochondrial complexes I and IV were decreased as well as membrane potential and ATP levels. On the contrary, ROS production increased. These effects seem to be age dependent and correlate with the corresponding Aβ and tau histopathologies. Based on these preliminary findings, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder distinct from that caused by Aβ. Moreover, we hypothesize that the both Alzheimer's proteins, tau and Aβ, seem to act in a synergistic or additive way on proteins/enzymes involved in energy metabolism and on mitochondrial respiration chain function leading to/accelerating neuron's demise.