Oxidative Stress Kinase Activation and Impaired Insulin Receptor Signaling Precede Overt Alzheimer’s Disease Neuropathology

Abstract

Background: The cascade of events that lead to Alzheimer’s disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. Objective: We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. Methods: Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). Results: ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRβ, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. Conclusion: We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology.