Inhibiting PI3K leads to glucose metabolism disturbance in default mode network

Abstract

BackgroundAs the symbolic pathological changes of Alzheimer’s disease (AD), hyperphosphorylated tau and amyloid plaque play important roles in the progression of the disease. In AD patients, the neural activity in default mode network is abnormal at different stages of the disease, and showed a hypoconnective status. Inhibition of phosphatidylinositol-3-kinase (PI3K) activates glycogen synthase kinase 3 beta (GSK-3β) and induces tau phosphorylation. ObjectiveWe speculated that inhibiting cerebral PI3K altered the glucose metabolism in DMN. We aimed to explore the impacts of PI3K inhibition on tau phosphorylation, cerebral glucose metabolism, and synaptic plasticity. MethodsWe injected wortmannin, an inhibitor of PI3K, lateral ventricularly in rats to mimic the pathology of AD. Immunohistochemistry was carried out to analyze the expression of phosphorylated tau. Region-specific glucose metabolism in the brain was analyzed using 18F-FDG PET imaging. In vivo long-term potentiation (LTP) in the hippocampus was detected to assess the synaptic plasticity. ResultsThe results show that the phosphorylated tau at T231 increased and the hippocampal LTP was suppressed 24 h after wortmannin administration. In the DMN, glucose uptake was significantly high, indicating a neural activity disturbance. ConclusionWe conclude that targeting PI3K-GSK-3β pathway to mimic AD tau pathology interrupted the glucose metabolism of DMN brain regions.