Insulin inhibits amyloid β-induced cell death in cultured human brain pericytes

Rensink, Annemieke A.M.; Otte-Höller, Irene; Boer, Roelie de; Bosch, Remko R.; Donkelaar, Hans J. ten; Waal, R.M.W. de; Verbeek, Marcel M.; Kremer, Berry

doi:10.1016/s0197-4580(03)00039-3

Cited by 66 publications

(43 citation statements)

References 36 publications

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“…We also found that the cell surface expression of the IRa was reduced in infected N2aC24L1-3 and ScN2a cells and in infected mouse brains, and that autophosphorylation of the IRb was suppressed in infected N2aC24L1-3 cells after stimulation with insulin. Reduced insulin signalling is suggested to be involved in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, by reducing its neuroprotective function and dysregulating synaptic plasticity and memory formation [14][15][16][17][18][19][20][21] . …”

Section: Discussionmentioning

confidence: 99%

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Prions disturb post-Golgi trafficking of membrane proteins

et al. 2013

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Section: Discussionmentioning

confidence: 99%

“…Insulin signalling may regulate a neuroprotective function, synaptic plasticity and memory formation [14][15][16][17][18][19][20][21] . Loss-of-function for attractin causes prion disease-like spongiform neurodegeneration in animals 22 .…”

mentioning

confidence: 99%

Prions disturb post-Golgi trafficking of membrane proteins

et al. 2013

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“…Consequently, insulin could play a role as a natural inhibitor of hIAPP-induced membrane damage. Recently, it was shown that insulin also protects cells against the cytotoxic action of Abeta, the peptide that forms amyloid fibrils in Alzheimer's disease (41). Interestingly, protection by insulin was connected to the ability of insulin to inhibit both Abeta fibril formation and Abeta-membrane interaction (41).…”

Section: Membrane Damage By Fibril Growth In Vivomentioning

confidence: 99%

“…Recently, it was shown that insulin also protects cells against the cytotoxic action of Abeta, the peptide that forms amyloid fibrils in Alzheimer's disease (41). Interestingly, protection by insulin was connected to the ability of insulin to inhibit both Abeta fibril formation and Abeta-membrane interaction (41). Inhibition of hIAPP-induced membrane damage by insulin, an efficient inhibitor of hIAPP fibril formation, is another argument for the causal role of hIAPP fibril growth.…”

Section: Membrane Damage By Fibril Growth In Vivomentioning

confidence: 99%

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

Engel

Khemtémourian²,

Kleijer³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

433

482

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Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulinproducing islet ␤ cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this ␤ cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.amylin ͉ amyloid cytotoxicity ͉ large unilamellar vesicles ͉ protein-membrane interaction ͉ type 2 diabetes mellitus T ype 2 diabetes mellitus (DM2) is characterized histopathologically by the presence of fibrillar amyloid deposits in the pancreatic islets of Langerhans. Amyloid cytotoxicity is thought to be an early mechanism involved in death of insulin-producing islet ␤ cells in DM2 (1). The main component of islet amyloid, and the actual fibril-forming molecule, is a 37-amino acid peptide called human islet amyloid polypeptide (hIAPP) or amylin, which is produced together with insulin in the pancreatic islet ␤-cells. It is thought that ␤ cells of DM2 patients are somehow killed through hIAPP-induced damage of the ␤ cell membrane (2). However, our knowledge of the mechanism of hIAPP-induced membrane damage is extremely sparse. It is not known how cytotoxic hIAPP species interact with cellular membranes and induce cell death. Furthermore, it is not established whether cytotoxic hIAPP species are formed before contacting the membrane or whether a membrane environment is in fact required for the formation of cytotoxic hIAPP species.The prevailing view is that membrane damage and concomitant ␤ cell death are caused by cytotoxic hIAPP oligomers (2-9). There are indications that these oligomers form ion channels (2, 3), as has been suggeste...

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“…Other studies indicate that insulin, interacting with Abeta, inhibits its fibrillar growth as shown in a cell-free assay and in the cell surface of human brain pericytes reducing the Abeta toxic effect [45]. Recently, it has been proposed that physiological insulin and pathological ADDLs are capable to regulate their mutual binding site abundance, creating a competitive balance between synapse survival and degeneration.…”

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confidence: 99%

Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease

Giacomazza¹,

Carlo²

2013

J Diabetes Metab

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Type 2 diabetes mellitus (T2DM) is a metabolic disorder in which insulin is no longer able to control the levels of blood sugar.A westernstyle diet in combination with the lack of exercise is the mainfactor for the increase of T2DM. While in the past people onlydeveloped T2DM at older age ("old age diabetes"), now even teenagerscontract T2DMbecause of the change in the lifestyle. Western diet is characterized by the exponential increase in the consumption of highly treated foods without appropriate nutrients for systemic metabolic functions or with added ingredients that prejudice protective actions of natural food constituent.T2DM is caused by insulin resistance in the tissues, no longer able to respond to the hormone action. It is most frequently associated with aging, a family history of diabetes, obesity, and failure of exercise.The insulin, ahormone produced by the beta-cells of the pancreas, is the key biomolecule for the regulation of carbohydrate and lipid metabolism. Although its action in body organs mainly concerns the glucose homeostasis, in Central Nervous System insulin performs several functions such as regulation of glucose metabolism, food intake and body weight, fertility and reproduction [1] and others not yet completely known. In particular, the high density of insulin receptors in the hippocampus and cerebral cortex regions has suggested its participation in learning and memory process. The administration of insulin to both humans and animal models has induced an enhancement of the memory function [2] and the treatment with insulin has given in several animal models beneficial effects to prevent memory loss after ischemia episodes whereas no effects are observed with glucose alone [3]. Insulin is also involved in the synaptic plasticity, for example, it as been show that insulin allows the long-lasting enhancement of GABA receptormediated synaptic transmission [4] and promote the internalization of AMPA receptors from the neuron synaptic membrane causing a long-term depression (LTD) of excitatory synaptic transmission in the hippocampus and cerebellum [5,6]. LTD is a process that, together with the opposite one, long-term potentiation has a great relevance for brain information storage and improvement of neurons links during development [7]. Furthermore, insulin receptor signaling regulates the maintenance of synapses and contributes to experience-dependent structural plasticity that is necessary for the recruitment of neurons into brain circuits [8]. Moreover, some studies suggest that insulin participates in neuronal differentiation of postnatal neural stem cell [9] and their culturing with both insulin and insulin-like growth factor (GF-1) causes a greater production of neurons during differentiation compared to culturesstimulated by IGF-1 alone [10].Insulin also avoids the necrosis of rat embryonic neurons cultured in a serum-free medium; in fact the protein was capable to restore the cell viability by activation of Protein Kinase C, having the crucial role of controlling other proteins ...

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Insulin inhibits amyloid β-induced cell death in cultured human brain pericytes

Cited by 66 publications

References 36 publications

Prions disturb post-Golgi trafficking of membrane proteins

Prions disturb post-Golgi trafficking of membrane proteins

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease

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