An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer's disease

Abstract

Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.