Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Drosophila Model of Tauopathy and Neuroblastoma Cells

Abstract

Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer’s disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our Drosophila models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3β, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic Drosophila models and cultured neuroblastoma cells.

Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain

“…Reduced expression of mRNAs for insulin (and other) signalling pathway molecules have been identified in astrocytes in association with the progression of AD neuropathological change [ 52 ]. Insulin resistance in neurones experimentally may also contribute to AD molecular pathology [ 10 , 68 ]. We also identified reduced expression of insulin signalling pathway genes in association with a DNA damage response in neurones in human autopsy tissue [ 51 ].…”

“…There appears to be a relationship between peripheral and central IR [ 69 ]. Neuronal IR has also been found in AD [ 37 , 57 ], and reduced insulin signalling can increase tau phosphorylation in experimental models [ 10 ]. However, Aβ molecular pathology may also affect insulin signalling [ 56 , 70 ].…”

The Role of Non-coding RNAs in Alzheimer’s Disease: From Regulated Mechanism to Therapeutic Targets and Diagnostic Biomarkers

“…miRNAs Regulate Insulin Signaling in Individuals With AD Recently, insulin signaling was shown to be involved in regulating neural plasticity and memory processing by protecting neurons from oxidative stress and apoptosis, which were determined to play crucial roles in the brains of patients with AD (Chen et al, 2016). Deregulation of insulin, insulin receptor, insulinlike growth factor (IGF-1), and other components of the insulin signaling pathway in the brain leads to memory impairment, tau hyperphosphorylation, and Aβ accumulation (Stohr et al, 2013;Chatterjee et al, 2019; Figure 2). Moreover, the effects of miRNAs on the insulin signaling pathway and insulin resistance has recently attracted attention (Chen et al, 2016).…”

Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer’s disease and other Tauopathies

“…This model of tauopathy displays a characteristic "rough-eye" phenotype that is caused by a massive loss of underlying photoreceptor neurons induced by human-Tau (hTau) overexpression, hyperphosphorylation and aggregation [73] [39]. Importantly, this model has been used extensively to identify enhancers and suppressors of hTauinduced toxicity [74] [75] [76]. Our data suggests that RI-AG03 can suppress hTau mediated degeneration in vivo as is evident in the dosedependent suppression of the "rough-eye" phenotype of treated Tau-expressing flies compared to age-matched untreated transgenics.…”