Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer disease

MARTINO ADAMI, PAMELA VICTORIA; QUIJANO, CELIA; MAGNANI, NATALIA; GALEANO, PABLO; EVELSON, PABLO ANDRÉS; CASSINA, ADRIANA; DO CARMO, SONIA; LEAL, MARÍA CELESTE; CASTAÑO, EDUARDO; CUELLO, AUGUSTO CLAUDIO; MORELLI, LAURA

Cairns

Congreso; 25th Biennial Meeting of the International Society for Neurochemistry; 2015

International Society for Neurochemistry (ISN); Asian Pacific Society for Neurochemistry (APSN); Australasian Neuroscience Society

Accumulation of amyloid beta, mitochondrial dysfunction and bioenergetic defects in nerve terminals have been linked to cognitive impairment that precedes Alzheimer disease (AD) onset. However, the hypothesis that synaptic bioenergetic deficiencies are associated with the progression of AD has not been proven in transgenic (Tg) mice models with AD-like phenotypes. To further explore this concept we performed a time-course analysis to assess brain mitochondrial function and synaptosomes bioenergetics in an animal model of early AD, the hemizygous (+/-) TgMcGill-RThy1-APP rat. Decrements in oxygen consumption rate and ATP synthesis along with oxidative damage were observed in hippocampal mitochondria of Tg(+/-) with aging. In addition, a decrease in the respiratory control ratio and spare respiratory capacity was found in mitochondria from synaptosomes of 6 month-old Tg(+/-) as compared to aged-matched control (WT) rats, that are associated with a decrease in complex I enzymatic activity. However, stereologic electron-microscopy did not show synaptic or mitochondrial changes in CA1 hippocampal region of Tg(+/-) as compared to WT. Cognitive impairments were prevented and bioenergetic deficits partially reverted when Tg(+/-) rats were fed a nutritionally complete diet from weaning to 6 month-old supplemented with pyrroloquinoline quinone, an antioxidant with cardio and neuroprotective effects. These results provide evidence that mitochondrial bioenergetic capacities of synaptosomes are not conserved in the Tg(+/-) McGill-R-Thy1-APP rats in a manner similar to that described in pathological human brain and reinforce the utility of this animal model as a platform for developing insights into the biological basis of early AD.