Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain

Abstract

Recent studies have suggested a possible role of insulin dysfunction in the pathogenesis of sporadic Alzheimer's disease (AD). In AD, brain glucose metabolism is impaired, and this impairment appears to precede the pathology and clinical symptoms of the disease. However, the exact contribution of impaired insulin signaling to AD is not known. In this study, by using a nontransgenic rat model of sporadic AD generated by intracerebroventricular administration of streptozotocin , we investigated insulin signaling , glucose transporters, protein O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain. We found impaired insulin signaling, overactivation of glycogen synthase kinase-3␤, decreased levels of major brain glucose transporters , downregulated protein O-GlcNAcylation , increased phosphorylation of tau and neurofilaments, and decreased microtubule-binding activity of tau in the brains of streptozotocin-treated rats. These results suggest that impaired brain insulin signaling may lead to overactivation of glycogen synthase kinase-3␤ and down-regulation of O-GlcNAcylation , which, in turn, facilitate abnormal hyperphosphorylation of tau and neurofilaments and, consequently, neurofibrillary degeneration. Alzheimer's disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia in, and eventually, death of the affected individuals. In less than 1% of cases, AD is caused by autosomal dominant mutations of presenilin-1, presenilin-2, or ␤-amyloid precursor protein. Most AD cases are sporadic and are believed to result from multiple etiologic factors including genetic susceptibility (such as the ApoE4 allele) and environmental and metabolic factors.1 One of these factors, impaired brain glucose metabolism, can be detected many years before the appearance of clinical symptoms of AD. 2 We recently found that altered OGlcNAcylation, an O-linked post-translational modification of nucleocytoplasmic proteins by a monosaccharide ␤-N-acetylglucosamine (O-GlcNAc), of the microtubuleassociated protein tau, links the impairment of brain glucose metabolism to hyperphosphorylation of tau.3,4 On the basis of these findings, we hypothesized that the impairment of brain glucose metabolism contributes to neurodegeneration via down-regulation of O-GlcNAcylation, which is regulated by glucose metabolism, and the resultant abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration in AD. 5Peripheral glucose metabolism is mainly regulated by insulin. Recent studies have indicated that insulin signaling also regulates glucose metabolism in the brain and plays important roles in neural development and neuronal activities and affects learning and memory. 6 The role of possible insulin dysfunction in AD has been suggested

Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease

“…These changes could be speculated to be caused by a decreased stability and/or increased degradation of IDE protein since they have not been associated with changes in IDE mRNA expression which remained unchanged in this acute phase, although we have not measured IDE activity which might be changed as well. Our data are in line whit Deng et al (2009) who has demonstrated decrement in the expression of IDE protein and its activity in HPC 3 weeks after the STZ-icv treatment.…”

“…Decreased p/t GSK-3ß ratio has been reported in a period up to 1 month after the STZ-icv treatment by others as well (Deng et al 2009;Shonsey et al 2012;Young et al 2014). However, in our experiments, this GSK-3β activation has not resulted in increased tau protein phosphorylation (PHF1) at this time-point when decreased p/t tau ration was found.…”

“…STZ-icv model has additionally been reported to develop also cerebral amyloid angiopathy in rats (appearing at 3 months and progressing up to 9 months after the STZ-icv) (Salkovic-Petrisic 2006;Salkovic-Petrisic 2011) and congophyllic amyloid deposition in mice (1 month after STZ-icv) (Sodhi et al 2013, Wang et al2014 as well as increased hippocampal APP mRNA after 4 weeks in rats (de la ) and normal APP mRNA expression 5 months after STZ-icv treatment in monkeys (Lee et al 2014, Park et al 2013). All were explored in STZ-icv model mostly at one time point only, usually up to 1 or 3 months after the STZ-icv treatment in rats and mice (Agrawal et al 2010, Agrawal et al 2011, Schido et al 2013, Deng et al 2009, Sodhi et al 2013, Wang et al 2014, Chen et al 2013Chen et al2014) and up to 5 months in monkeys (Lee et al 2014;Park et al, 2013;Heo et al 2011). Periods longer than 5 months post-STZ-icv injection have not been explored in regard to the brain insulin system in STZ-icv model of sAD.…”

Insulin Receptor Signaling in Cones

“…The phosphorylation status in Nrl Ϫ/Ϫ mouse retina was set at 100%. deficient brain insulin signaling pathway in Alzheimer disease and diabetes has recently been reported (75,76).…”

O-GlcNAcylation of AMPA Receptor GluA2 Is Associated with a Novel Form of Long-Term Depression at Hippocampal Synapses

“…Despite these observations, our understanding of the physiological role of O-GlcNAcylation in modulating brain function remains remarkably limited. To date, only a handful of studies exist examining O-GlcNAcylation in the nervous system, with most focusing on the relationship between decreased O-GlcNAcylation and hyperphosphorylation of tau in Alzheimer's disease (AD; Yuzwa et al, 2008;Deng et al, 2009;Yuzwa and Vocadlo, 2009). Because synaptic efficacy is highly regulated by serine/threonine phosphorylation/dephosphorylation of synaptic proteins (Malenka and Bear, 2004), it is possible that O-GlcNAcylation, which also occurs on serine/threonine residues, is as important as phosphorylation in modulating synaptic function.…”