Early mitochondrial dysfunction and behavioral alterations in a new transgenic rat model of presymptomatic Alzheimer's disease

MARTINO ADAMO PAMELA V; MAGNANI NATALIA; GALEANO PABLO; ROTONDARO CECILIA; CUELLO A CLAUDIO; EVELSON PABLO; CASTAÑO EDUARDO; MORELLI LAURA

Buenos Aires

Congreso; VIII International congress Society for Free Radicals Biology and Medicine South American Group; 2013

Society for Free Radicals Biology and Medicine South American Group

Intraneuronal accumulation of amyloid-beta (AB) has been linked to mild cognitive impairment that precedes Alzheimer´s disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous (+/-) transgenic (Tg) rats (McGill-R-Thy1-APP). We performed in Tg(+/-) and control (WT) rats a time-course analysis of the bioenergetic profile in cognitive areas of the brain to assess the impact of mitochondria functionality on behavior. We measured AB levels and performed respirometric and ATP synthesis assays with isolated mitochondria from cortex and hippocampus. Oxidative stress markers (TBARS and 8-OHdG) were evaluated. Behavior was tested with Elevated Plus Maze, Open Field, Novel Object Recognition, Y-maze and Morris Water Maze protocols. We found in 3 month old Tg(+/-) rats as compared to WT alterations in respiratory chain functionality and deficient oxidative phosphorylation associated to mitochondrial AB accumulation, higher levels of anxiety and spatial reference memory impairment. However, episodic-like memory, working memory and spatial learning were preserved. A clear mitochondrial dysfunction was observed in older Tg(+/-) rats characterized by lower oxygen consumption rate and increments in reactive oxygen species. The phenotype of young Tg(+/-) rats will help to test early therapeutic interventions to modulate mitochondrial AB levels, neuropathology and behavior.