Figure 7. Graphical summary of the model of Aβ pathology in GRU102.

Pan-neuronal Aβ expression leads to an imbalance between reactive oxygen species (ROS) production and antioxidant (AOX) defense, resulting in oxidative stress as an early event in GRU102. Increase in mitochondrial protein carbonyl content (mtPCC) was also observed as an early phenomenon in GRU102. Elevated oxidative stress further affects ROS-sensitive Tricarboxylic Acid (TCA) cycle enzyme, including alpha-ketoglutarate dehydrogenase (aKGDH), resulting in a reduction of its activity as well as altered levels of TCA metabolites (aKGDH, fumarate and malate) in old GRU102. Together with the reduction in electron transfer chain (ETC) complex I and IV activities as well as low ATP levels in the GRU102 animals we reported previously (Fong et al., 2016), these phenomena result in metabolic stress. Proteostasis, an energy-intensive process, is impaired by metabolic and oxidative stress, resulting in an increase in general protein aggregates. Treatment with Metformin (Met) increases stress resistance and rescues metabolic defects of GRU102. Metformin-treated GRU102 also appears to reduce the increase in protein aggregates in GRU102, even though it could not fully rescue this phenotype.