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

Han, Xiaobin; Yang, Liling; Du, Heng; Sun, Qinjian; Wang, Xiang; Liu, Cong; Liu, Xiaohui; Yin, Ling; Li, Shan; Du, Yifeng

doi:10.1007/s10571-015-0268-5

Cited by 23 publications

(32 citation statements)

References 54 publications

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“…Furthermore, regulation of prion diseases pathway by miR-27a, miR-146a, and miR-155, reinforces the hypothesis that AMD can be a protein misfolding disease, such as AD, due to deposition of Aβ oligomers in drusen bodies. The potential link between AMD and AD is also in line with the deregulation of insulin receptor signaling by miR-27a, miR-146a, and miR-155 (Giuffrida et al, 2012; Gontier et al, 2015; Takach et al, 2015; Han et al, 2016; Sajan et al, 2016; Table 4A). The set of miRNAs differentially expressed in AMD patients can regulate the same pathways of miRNAs dysregulated in the animal model of AMD (Figure 4 and Table 4B).…”

Section: Resultsmentioning

confidence: 75%

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

et al. 2017

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Age related macular degeneration (AMD) is the leading cause of blindness among people aged 50 and over. Retinal deposition of amyloid-β (Aβ) aggregates in AMD patients has suggested a potential link between AMD and Alzheimer's disease (AD). We have evaluated the differential retinal expression profile of miRNAs in a rat model of AMD elicited by Aβ. A serum profile of miRNAs in AMD patients has been also assessed using single TaqMan assay. Analysis of retina from rats intravitreally injected with Aβ revealed that miR-27a, miR-146a, and miR-155 were up-regulated in comparison to control rats. Seven miRNA (miR-9, miR-23a, miR-27a, miR-34a, miR-126, miR-146a, and miR-155) have been found to be dysregulated in serum of AMD patients in comparison to control group. Analysis of pathways has revealed that dysregulated miRNAs, both in the AMD animal model and in AMD patients, can target genes regulating pathways linked to neurodegeneration and inflammation, reinforcing the hypothesis that AMD is a protein misfolding disease similar to AD. In fact, miR-9, miR-23a, miR-27a, miR-34a, miR-146a, miR-155 have been found to be dysregulated both in AMD and AD. In conclusion, we suggest that miR-9, miR-23a, miR-27a, miR-34a, miR-146a, miR-155 represent potential biomarkers and new pharmacological targets for AMD.

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Section: Resultsmentioning

confidence: 75%

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

et al. 2017

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“…Once cells were differentiated, all subsequent treatments and experiments were carried out in DMEM without FBS. The dose of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and treatment times were chosen considering glial fibrillary acidic protein levels as the indicator of reactive astrocytes (data not shown). Likewise, we used HT concentration that should be of physiological relevance [32] and that did not induce cytotoxicity [41].…”

Section: Cell Differentiation and Treatment Of Astrocytesmentioning

confidence: 99%

“…All membranes were incubated with the primary antibodies (diluted 1:1000) in blocking buffer at 48C overnight. The membranes were washed three times with TTBS and incubated with the corresponding secondary antibody Experimental groups originating from different treatment combinations with hydroxytyrosol (HT) 5 mM for 2 h (pre-treatment) and/or 24 h (posttreatment), and treatment for 24 h with amyloid b peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) BioFactors conjugated with horseradish peroxidase (Thermo Fisher Scientific, Inc., Waltham, MA) at a dilution of 1:2,000 or 1:5,000 depending on primary antibody, in nonfat milk during 90 min at 258C. All proteins were detected by chemiluminescence using an ECL system (PerkinElmer Life Sciences, Boston, MA) and quantified by densitometry using Adobe Photoshop's (Adobe systems, Inc., Mountain View, CA).…”

Section: Western Blottingmentioning

confidence: 99%

“…Therefore, this fragment represents the core where Ab is deposited [8]. Moreover, the amino-acid sequence of Ab can be divided into different functional domains, such as the C-terminus of Ab(1-42) (which has a fragment of 11 amino-acids) and the (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) domain, which is responsible for cytotoxicity and shares with Ab(1-42) the ability to selfaggregate [9].…”

Section: Introductionmentioning

confidence: 99%

“…Both oligomers and deposits of Ab, among others, can trigger astrogliosis in the AD brain [25]. Furthermore, recent studies carried out in human astrocytes have shown that Ab(1-42) impairs insulin signaling and glycogen storage [26,27].…”

Section: Introductionmentioning

confidence: 99%

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Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease

et al. 2017

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Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 43(4):540-548, 2017.

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Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats

et al. 2015

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Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-β, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance.

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

Cited by 23 publications

References 54 publications

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease

Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats

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