神経学的障害

Dysregulation of Insulin Signaling in Human AD Brain and Alleviation of Aβ-Induced Insulin Resistance by Amyloid-β Binding Peptide (ABP) in Neural Cells

Abstract

Yuka Sai , Balu Chakravarthy, Debbie Callaghan, Qiao Li and Wandong Zhang

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β peptides (Aβ) and intraneuronal neuro-fibribillary tangles in the brain. Increasing evidence builds a strong case for the role of soluble Aβ oligomers (AβOs) in the impairment of insulin signaling in AD. Insulin signaling pathway begins upstream at the insulin receptor by phosphorylating IRS1 and propagating the signal downstream to the PI3K/ Akt which down-regulates GSK3β activity for tau phosphorylation and activates mTORC1 that mediates a wide range of cellular functions. Our study found that human AD brains had high levels of Aβ peptides with cerebral amyloid angiopathy (AD/CAA) and showed low activities of insulin signaling-responsive transcription factors as compared to age-matched non-demented controls (ND). Our further studies with neuroblastoma 2a (N2a) cells stably transfected with a human AβPP695 gene (N2a-AβPP), which secrete excessive Aβ, show that the basal levels of the expression and phosphorylation of several but not all critical signaling proteins along insulin signaling pathway are dysregulated as compared to the parental N2a cells. N2a-AβPP cells were phenotypically insulin resistant in response to insulin stimulation. Pre-treatment of N2a-AβPP cells with the Aβ-binding peptide (ABP), which binds and removes Aβ oligomers, significantly enhanced insulin signaling response in cells compared to controls. Taken together, our data suggest that human AD/CAA brains had dysregulation of insulin signaling and that Aβ oligomers may be responsible for inducing the insulin-resistant phenotype in N2a-AβPP cells and the removal of Aβ oligomers by ABP improved insulin signaling and relieved insulin resistant phenotype.