Long-term abnormalities in brain glucose/energy metabolism after inhibition of the neuronal insulin receptor: implication of tau-protein.

Abstract

The triplicate intracerebroventricular (icv) application of the diabetogenic compound streptozotocin (STZ) in low dosage was used in 1-year-old male Wistar rats to induce a damage of the neuronal insulin signal transduction (IST) system and to investigate the activities of hexokinase (HK), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GDH), pyruvate kinase (PK), lactate dehydrogenase (LDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) in frontoparietotemporal brain cortex (ct) and hippocampus (h) 9 weeks after damage. In parallel, the concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine triphosphate (GTP) and creatine phosphate (CrP) were determined. We found reductions of HK to 53% (ct) and 60% (h) of control, PFK to 63/64% (ct/h); GDH to 56/61% (ct/h), PFK to 57/59% (ct/h), alpha-KGDH to 37/35% (ct/h) and an increase of LDH to 300/240% (ct/h). ATP decreased to 82/87% (ct/h) of control, GTP to 69/81% (ct/h), CrP to 82/81% (ct/h), approximately P to 82/82% (ct/h), whereas ADP increased to 189/154% (ct/h). The fall of the activities of the glycolytic enzymes HK, PFK, GDH and PK was found to be more marked after 9 weeks of damage when compared with 3- and 6-week damage whereas the diminution in the concentration of energy rich compound was stably reduced by between 20 and 10% relative to control. The abnormalities in glucose/energy metabolism were discussed in relation to tau-protein mismetabolism of experimental animals, and of sporadic AD.