SFRR-Europe Annual Award Lecture: Redox Biology and Metabolism in Brain Aging and Alzheimer׳s Disease

Abstract

The gradual decline in energy metabolism during brain aging and some neurodegenerative disorders results in a hypometabolic state, which is a function of deficits in (a) substrate supply, (b) mitochondrial catalysis and energy transduction, and b) cytosolic metabolic, signaling, and transcriptional pathways. Mitochondria play a central role for they integrate several signaling processes and generate molecules such as H2O2 that coordinate cytosolic signaling and transcriptional pathways through thiol/disulfide exchange mechanisms. The hypometabolic state inherent in brain aging and a mouse model of Alzheimer׳s disease was examined in a model that integrates mitochondrial function, insulin signaling, and JNK signaling as well as the effects of nutraceutical interventions –likely acting through thiol/disulfide exchange mechanisms– in the regulation of these parameters. Brain aging proceeds with a decrease of glucose uptake (dynamic microPET imaging), which was associated with a decrease in the expression of the insulin-sensitive neuronal GLUT3/4 and microvascular endothelium GLUT1 (55 kD) but not astrocytic GLUT1 (45 kD). Brain aging was associated with an imbalance between the PI3K/Akt pathway of insulin signaling and JNK signaling and a down-regulation of the PGC1α-mediated transcriptional pathway of mitochondrial biogenesis, thus impairing on several aspects of energy homeostasis. Of note, these effects were observed in cortex- and hippocampal preparations but they are not necessarily cell specific, for astrocytes respond in a different manner: astrocytes showed an age-dependent increase in mitochondrial oxidative metabolism (respiring either on glucose or glucose plus pyruvate) and mitochondrial biogenesis. These metabolic changes were associated with an age-dependent increase in H2O2 generation (largely ascribed to NOX2) and NFκB signaling as well as augmented responses with age to inflammatory cytokines. Further, these inflammatory cytokines, IL-1β and TNFα stimulated mitochondrial oxidative metabolism and mitochondrial biogenesis in astrocytes. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity are the major characteristics of the triple transgenic mouse model of Alzheimer׳s disease. These effects were accompanied with diminished membrane translocation of GLUT4 and GLUT3, increase in tyrosine phosphorylation of the IRS (inactivation) and decrease in serine phosphorylation (activation). The former effect coincided with increased activation of JNK1 and diminished activation of Akt. The JNK/Akt imbalance affected mitochondrial energy metabolism. The functional outcome of this hypometabolic state was translated into a substantially diminished long-term potentiation. The hypometabolic state in both models, brain aging and the mouse model of Alzheimer׳s disease, was rescued by treatment with lipoic acid, likely through a thiol/disulfide mechanism, that resulted largely in activation of the insulin receptor substrate and higher translocation to the membrane of the insulin-sensitive glucose transporters. In this manner, lipoic acid treatment appears to increase substrate supply; its effectiveness resulted in an increase of synaptic plasticity measured as long-term potentiation.