Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Stöhr, Oliver; Schilbach, Katharina; Moll, Lorna; Hettich, Moritz M.; Freude, S.; Wunderlich, Frank; Ernst, Marianne B.; Zemva, Johanna; Brüning, Jens C.; Krone, Wilhelm; Udelhoven, Michael; Schubert, Markus

doi:10.1007/s11357-011-9333-2

Cited by 62 publications

(39 citation statements)

References 70 publications

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“…The association of AD with insulin resistance (39), type 2 diabetes (16-18, 40, 41), reduced insulin concentration in the cerebrospinal fluid (23,39), and cognition improvement after intranasal insulin administration (23,24,39) are some of the clinical evidence suggesting that a defective insulin action may contribute to the pathogenesis of AD. Studies in experimental animals (42)(43)(44) and in cultured cells (45,46) confirm that insulin-signaling impairment leads to abnormal APP processing and A␤ accumulation; the underlying molecular mechanisms, however, remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells

et al. 2013

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Alzheimer's disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mechanism is not clear. We analyzed the effect of insulin on several molecular steps of amyloid precursor protein (APP) processing and β-amyloid (Aβ) intracellular accumulation in a panel of human neuronal cells and in human embryonic kidney 293 cells overexpressing APP-695. The data indicate that insulin, via its own receptor and the phosphatidylinositol-3-kinase/AKT pathway, influences APP phosphorylation at different sites. This rapid-onset, dose-dependent effect lasts many hours and mainly concerns dephosphorylation at the APP-T668 site. This effect of insulin was confirmed also in a human cortical neuronal cell line and in rat primary neurons. Cell fractionation and immunofluorescence studies indicated that insulin-induced APP-T668 dephosphorylation prevents the translocation of the APP intracellular domain fragment into the nucleus. As a consequence, insulin increases the transcription of antiamyloidogenic proteins such as the insulin-degrading enzyme, involved in Aβ degradation, and α-secretase. In contrast, the transcripts of pro-amyloidogenic proteins such as APP, β-secretase, and glycogen synthase kinase (Gsk)-3β are decreased. Moreover, cell exposure to insulin favors the nonamyloidogenic, α-secretase-dependent APP-processing pathway and reduces Aβ40 and Aβ42 intracellular accumulation, promoting their release in the extracellular compartment. The latter effects of insulin are independent of both Gsk-3β phosphorylation and APP-T668 dephosphorylation, as indicated by experiments with Gsk-3β inhibitors and with cells transfected with the nonphosphorylatable mutated APP-T668A analog. In human neuronal cells, therefore, insulin may prevent Aβ formation and accumulation by multiple mechanisms, both Gsk-3β dependent and independent.

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Section: Discussionmentioning

confidence: 99%

Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells

et al. 2013

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“…These results suggest that insulin dysfunction may not only be a consequence of AD pathology but also may be playing a causal role in triggering or perhaps in facilitating the disease process and perhaps rate of progression. It is becoming increasingly apparent that alteration of signaling molecules that are known to be involved in insulin signal transduction may play a role in the pathogenesis of AD (Correia et al, 2012;Dominguez et al, 2008;Stockhorst et al, 2004;Stohr et al, 2013). Although the actions of brain insulin are not fully understood, binding of insulin to its receptor initiates autophosphorylation of the receptor's β-subunit, leading to binding and tyrosine phosphorylation of multiple insulin receptor substrates including IRS-1 and IRS-2, which play a role in synaptic plasticity and memory formation (Freiherr et al, 2013;Moloney et al, 2010).…”

Section: Article In Pressmentioning

confidence: 99%

Geniposide attenuates insulin-deficiency-induced acceleration of β-amyloidosis in an APP/PS1 transgenic model of Alzheimer’s disease

Zhang

Yin

Liu

et al. 2015

Neurochemistry International

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“…In line with this, intranasal insulin administration has been effective in enhancing cognitive performance in healthy humans and some patients with AD [74,75] and in improving memory formation in rodents [76], which may include regulation of glucose uptake and/or metabolism [77]. In contrast, decreases in insulin or IGF-1 signalling in rodent models of AD triggered reductions in Aβ deposition and in cognitive performance [78][79][80][81]. In…”

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confidence: 92%

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Duarte¹

2014

aging dis

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From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer's disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS).Key words: Neurodegeneration, Diabetes, Alzheimer's disease, Insulin, Metabolism Diabetes mellitus can be defined as a chronic metabolic disorder characterized by hyperglycaemia, resulting from inappropriate insulin secretion and/or action [1]. The vast majority of the diabetes cases are included in two main categories, classified according to the underlying cause, which are type 1 diabetes (T1D) or insulindependent diabetes, generally caused by an autoimmune reaction to antigens of pancreatic β-cells, leading to impaired insulin production, and type 2 diabetes (T2D) or insulin-resistant diabetes, characterised by inefficiency of insulin action. While T1D is mainly observed in children and adolescents, T2D is more common among adults, accounting for more than 90% of the diabetes cases worldwide. The prevalence of diabetes and impaired glucose tolerance achieved now epidemic proportions, respectively at 6.9% and 8.3% of the world population, and predicted to raise to 8. 0% and 10.1% in 2035 [2]. Moreover, diabetes is nowadays a leading cause of death accounting for 8.4% of global mortality in people aged between 20 and 79 years [2]. The main contributor for the high prevalence of diabetes is the rise of obesity, related to the combination of ample food availability and a sedentary lifestyle, contrasting to less abundant food supplies and higher physical activity observed until a century ago.Diabetes is associated with the occurrence of well described microvascular complications that affect different organs, leading most commonly to retinopathy, nephropathy and peripheral neuropathy, which development is dependent on the duration of the disease and glycaemia control [3]. When the control of the disorder allowed patients to live longer and without these Volume 6, N...

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Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Cited by 62 publications

References 70 publications

Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells

Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells

Geniposide attenuates insulin-deficiency-induced acceleration of β-amyloidosis in an APP/PS1 transgenic model of Alzheimer’s disease

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

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