Deregulation of brain insulin signaling in Alzheimer’s disease

Chen, Yanxing; Deng, Yanqiu; Zhang, Baorong; Chen, Gong

doi:10.1007/s12264-013-1408-x

Cited by 73 publications

(47 citation statements)

References 149 publications

(137 reference statements)

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“…In addition, insulin can attenuate pathogenic binding of Aβ and synaptic deficits (Chen et al 2014). Although insulin mRNA and insulin protein synthesis is not measurable in astrocytes, these glial cells could be influenced by insulin (Henneberger et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…It is critical for memory processing, synaptic genesis and remodeling. Furthermore, insulin is a kind of neuroprotective hormone that contributes not only to metabolism but also to cognition (Chen et al 2014). Several recent reports have indicated that both brain IR density and insulin level decrease with age (Cole and Frautschy 2007; Laron 2009) and many key substrates in the insulin signal transduction pathway are significantly reduced in AD (Liu et al 2011; Pearson-Leary and McNay 2012).…”

Section: Introductionmentioning

confidence: 99%

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Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Han

Yang

et al. 2015

Cell Mol Neurobiol

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The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer’s disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1–42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1–42 oligomers in a dose-dependent manner (p < 0.05) and this trend could be recovered by insulin treatment (p < 0.05). However, the expressions of total Akt and mTOR were invariant (p > 0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1–42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Han

Yang

et al. 2015

Cell Mol Neurobiol

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“…As well as occurring with insulin signaling, it has been found that impairment of cerebral glucose metabolism could occur in the early stages of AD, and deteriorate with the progression of the disease (Shah, Desilva, & Abbruscato, ; Chen, Deng, Zhang, & Gong, ). Compared to peripheral organs, the availability of glucose and other nutrients for neural tissues is limited by the dynamic restrictive properties of the BBB (Chiaravalloti et al, ; Keeney, Ibrahimi, & Zhao, ).…”

Section: Alzheimer Diseasementioning

confidence: 99%

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

Rojas-Gutierrez

Muñoz-Arenas

Treviño

et al. 2017

Synapse

149

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Alzheimer's disease (AD) is the most common cause of dementia and one of the most important causes of morbidity and mortality among the aging population. AD diagnosis is made post-mortem, and the two pathologic hallmarks, particularly evident in the end stages of the illness, are amyloid plaques and neurofibrillary tangles. Currently, there is no curative treatment for AD. Additionally, there is a strong relation between oxidative stress, metabolic syndrome, and AD. The high levels of circulating lipids and glucose imbalances amplify lipid peroxidation that gradually diminishes the antioxidant systems, causing high levels of oxidative metabolism that affects cell structure, leading to neuronal damage. Accumulating evidence suggests that AD is closely related to a dysfunction of both insulin signaling and glucose metabolism in the brain, leading to an insulin-resistant brain state. Four drugs are currently used for this pathology: Three FDA-approved cholinesterase inhibitors and one NMDA receptor antagonist. However, wide varieties of antioxidants are promissory to delay or prevent the symptoms of AD and may help in treating the disease. Therefore, therapeutic efforts to achieve attenuation of oxidative stress could be beneficial in AD treatment, attenuating Aβ-induced neurotoxicity and improve neurological outcomes in AD. The term inflammaging characterizes a widely accepted paradigm that aging is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses in the absence of overt infection, and is a highly significant risk factor for both morbidity and mortality in the elderly.

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“…Insulin is an important long-term neuroprotectant, and severe lack of it leads to neurodegeneration [49]. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD [50]. Intrahippocampal insulin injection in normal rats significantly improves spatial memory ability [51].…”

Section: Insulin Can Improve Cognitive Dysfunction Caused By Insulin mentioning

confidence: 99%

Insulin resistance and cognitive dysfunction

Wang

2015

Clinica Chimica Acta

105

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Deregulation of brain insulin signaling in Alzheimer’s disease

Cited by 73 publications

References 149 publications

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

Insulin resistance and cognitive dysfunction

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