Impact of pyrroloquinoline quinone on synaptic bioenergetic status, cognition and behavior in a transgenic rat model of early Alzheimer?s disease

MORELLI LAURA

Congreso; Dementia 2014; 2014

Alzheimer?s disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. Previous reports showed no consistent time-course bioenergetic deficiencies of cortical and hippocampal presynaptic nerve terminals (synaptosomes) from commonly used mouse models with AD-like phenotypes (J20, Tg2576 and APP/PS) as compared to age-matched controls supporting the conclusion that the intrinsic bioenergetic capacities of presynaptic nerve terminals are maintained in these symptomatic AD mouse models. Intraneuronal accumulation of amyloid â (iAâ) has been linked to mild cognitive impairment that precedes AD onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous (+/-) transgenic (Tg) McGill-R-Thy1-APP rat. In addition to iAâ Tg(+/-) rats show a wide array of behavioral and cognitive impairments from young adulthood (3 month-old) to middle-age (12 month-old). We performed a time-course analysis of in vivo brain metabolism, mitochondrial functionality, reactive oxygen species (ROS) generation, lipid peroxidation (TBARS), protein nitrosylation, mitochondrial DNA (mDNA) oxidation/deletion and energetic metabolism genes expression. We detected by microPET imaging and 18F-fluoro-2-deoxy-D-glucose (18F-FDG) a clear hypometabolism in brains of 6 month old Tg(+/-) as compared to WT rats. These phenotype correlates with bioenergetic dysfunctions observed in isolated mitochondria from hippocampus including decrements in ATP synthesis rate and increments in ROS and TBARS production. In addition, in situ respirometer assays showed decrements in the respiratory control ratio (RCR), spare respiratory capacity (SRC) and ATP synthesis in synaptosomes isolated from Tg(+/-) and WT rats. By contrast, no significant differences were detected by stereologic electron microscopy in the amount of synapses or number/size and shape of mitochondria in CA1 hippocampal region of 6 month old Tg(+/-) and WT rats. Bioenergetic deficiencies in hippocampal synaptosomes and the impairments in working memory and spatial reference memory were partially reverted when Tg(+/-) rats were fed a nutritionally complete diet from weaning to 6 months-old with pyrroloquinoline quinone, a mitochondrial biogenesis stimulator with antioxidant, cardio and neuroprotective effects. Our results support that, in agreement with human AD brain, the intrinsic bioenergetic capacities of presynaptic nerve terminals are not conserved in the Tg(+/-) McGill-R-Thy1-APP rats suggesting that the energetic synaptic dysfunction is an early event, independent of extracellular Aâ accumulation or synaptic loss and plausible to be modulated by mitochondrial functionality.