Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling

Abstract

Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe 2+ ) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor β (IRβ), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the in vivo studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our in vitro work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading.

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

“…The previous studies have demonstrated that anaesthesia has a significant impact on phosphorylation of tau and on neuropathology of cognitive decline in Alzheimer's disease [47]. A recent study has addressed that iron deposition leads to hyperphosphorylation of tau and impairs cognition in mic e [48]. Thus, hyperphosphorylation of tau, as a result of iron overload, is supposed to be another mechanism of GA-induced cognitive deficits.…”

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

“…Indeed, excess neuronal iron can promote tau hyperphosphorylation and facilitate the formation of NFTs through cyclin-dependent kinase (CDK5)/P25 complex and GSK-3β kinase pathways (Guo et al, 2013;Vossel et al, 2015;Kim et al, 2018;. Additionally, the study also shows that dysfunctional insulin signaling is associated with iron-induced abnormal phosphorylation of tau in AD (Wan et al, 2019).…”

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

“…The previous studies have demonstrated that anesthesia has a significant impact on phosphorylation of tau and on neuropathology of cognitive decline in Alzheimer's disease [47]. A recent study has addressed that iron deposition leads to hyperphosphorylation of tau and impairs cognition in mice [48]. Thus, hyperphosphorylation of tau, as a result of iron overload, is supposed to be another mechanism of GA-induced cognitive deficits.…”