Reevaluating Metabolism in Alzheimer's Disease from the Perspective of the Astrocyte-Neuron Lactate Shuttle Model

Figure 2

Aerobic glycolysis in A𝛽-resistant cells. The stabilization of hypoxia-inducible factor 1 𝛼 (HIF1𝛼) in amyloid beta- (A𝛽-) resistant cells stimulates increased expression of glucose transporters and glycolytic enzymes thereby increasing the conversion of glucose to pyruvate. Additionally, HIF-1 induces the transcription of lactate dehydrogenase A (LDHA), resulting in an increase in the conversion of pyruvate to lactate. Furthermore, HIF-1 suppresses mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase (PDH) resulting in decreased flux through the tricarboxylic acid (TCA) cycle and repressed oxidative phosphorylation (OXPHOS). Decreased OXOPHOS attenuates mitochondrial ROS production rendering cells more resistant to apoptosis in the presence of A𝛽. In cells failing to undergo aerobic glycolysis, increased mitochondrial respiration potentiates A𝛽-mediated ROS production to toxic levels resulting in cell death.