Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex

Ohtake, Nobuaki; Saito, Mieko; Eto, Masashi; Seki, Kenjiro

doi:10.1016/j.regpep.2014.04.003

Cited by 33 publications

(32 citation statements)

References 54 publications

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“…We previously reported that exendin-4, a potent agonist of the GLP-1 receptor (GLP-1R), promotes the up-regulation of the membrane AMPA receptor GluR1 subunit through the activation of cAMP response element-binding protein (CREB) and that this process occurs via Gαs protein activation signaling in the mouse neocortex. Similar results were obtained with the intracerebroventricular administration of Aβ oligomer [14]. Moreover, we have also demonstrated that GLP-1 analogue administration such as liraglutide consistently enhances long-term potentiation (LTP) and reverses the impairments of LTP that are induced by β-amyloid fragments in the CA1 area of the hippocampus [15].…”

Section: Introductionsupporting

confidence: 84%

“…G protein-coupled receptors (GPCRs), including the Gαs, directly influence the amyloid cascade through the modulation of the α-, β-and γ-secretases, the proteolysis of the amyloid precursor protein (APP), and the regulation of amyloid-β degradation [19]. Although it has been suggested that the GLP-1R is not only coupled to the Gαs but also to the Gαi/Gαo type of G proteins [20], our previous findings suggested that exendin-4 promotes the CREB phosphorylation-independent up-regulation of ADAM10 in the plasma membrane fraction of the mouse neocortex, resulting in the up-regulation of the protein level of the mature form of ADAM10, an α-secretase of amyloid precursor protein (APP), indicating that the GLP-1R promotes the signaling pathway under the Gαs protein in the mouse neocortex [14]. Additionally, the stimulation of Gαs protein-coupled serotonin receptor 5-HT4 or pituitary adenylate cyclase-activating polypeptide type I receptor induced α-secretase activation; the agonist of this receptor has been considered to be a therapeutic strategy for AD treatment [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor

Ohshima¹

2015

AJBIO

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Glucagon-like peptide-1 receptor (GLP-1R) agonist treatment has the potential to be a novel therapeutic treatment for Alzheimer's disease (AD). We previously reported that exendin-4, a Gαs protein-coupled GLP-1R agonist, up-regulates the membrane AMPA receptor GluR1 subunit in the neocortex. However, it is uncertain whether GLP-1R agonists have an advantage as an AD treatment target compared with other Gαs protein-coupled receptors. Here we show that both the protein level of proglucagon, a precursor of GLP-1, and the immunoreactivity level of GLP-1 are significantly decreased in the medial prefrontal cortex (mPFC) of aged mice (14 months old) compared with young (3 weeks old) or adult (6 months old) mice, but not in area CA1, the dentate gyrus (DG) nor in the nucleus of the solitary tract. However, the protein and immunoreactivity levels of GLP-1R in the mPFC, DG and hippocampal CA1 and CA3 areas were preserved in the aged mice. We then confirmed whether the age-dependent decrease in GLP-1 in the mPFC was associated with the activity level or the number of microglial cells in the mPFC. Co-staining of CD11b and GLP-1 in the mPFC revealed that the number of CD11b-positive cells was increased in the aged mice. Moreover, lipopolysaccharide (LPS) injection increased the number of CD11b-positive cells in the mPFC, but the number of GLP-1-positive cells was unchanged. However, the number of CD11b-positive cells that co-localized with GLP-1R in the mPFC is increased by LPS and aging. Because the GLP-1R is preserved in aged mPFC, but the amount of GLP-1 produced in the brain region is diminished, and spatial cognitive memory was impaired in aged mice, we propose that treatment with GLP-1 analogues has great promise for rescuing and ameliorating the age-related mPFC-dependent decline of cognitive functions.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor

Ohshima¹

2015

AJBIO

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“…; Ohtake et al . ). Indeed, in SH‐SY5Y neuroblastoma cells, 1 h liraglutide treatment induced a more than 3‐fold increase in pCREB protein levels (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…On the other hand, and of interest to us, many studies have demonstrated that CREB is also pivotal in nerve cell survival as well as neuronal proliferation, differentiation and plasticity because of its mediation of gene expression (Lonze and Ginty 2002;Dragunow 2004;Sakamoto et al 2011). Using animal models, it has been demonstrated that stimulation of the GLP-1R pathway by either Ex-4 or liraglutide induces CREB activation in rodent brain (DellaValle et al 2014;Ohtake et al 2014). Indeed, in SH-SY5Y neuroblastoma cells, 1 h liraglutide treatment induced a more than 3-fold increase in pCREB protein levels (Fig.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice

Bader

Tamargo

et al. 2015

Journal of Neurochemistry

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Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI.

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“…Further studies are necessary to assess whether therapeutic methods for T2DM could antagonize the neurotoxicity of Aβ peptides and ameliorate symptoms of AD patients. Glucagon-like peptide-1 (GLP-1) is a T2DM novel therapeutic drug has been suggested as a therapeutic target for AD (5). Due to the relatively short half-life of native GLP-1, which is easily degraded by dipeptidyl peptidase-4 (DPP-4), it has been limited in its clinical application (6).…”

Section: Introductionmentioning

confidence: 99%

Exendin-4 antagonizes Aβ1-42-induced attenuation of spatial learning and memory ability

Wang¹,

Wang²,

Jiang³

et al. 2016

Experimental and Therapeutic Medicine

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β-amyloid protein (Aβ) accumulation in cerebral centers involved in cognition and memory is a pivotal pathological feature of Alzheimer's disease (AD). The onset process of type 2 diabetes mellitus (T2DM) has a number of similarities compared with AD. Thus, it is hypothesized that the pharmacological therapy employed for the treatment of T2DM may help to prevent and ameliorate the symptoms of AD. This study demonstrated that Exendin-4, which is a glucagon-like peptide-1 analogue which is used as a therapeutic drug for T2DM, markedly antagonized Aβ fragment-induced attenuation of spatial learning and memory ability, as indicated by a Morris water maze experiment. In addition, we investigated the potential underlying electrophysiological and molecular mechanisms. The results indicate that Exendin-4 rescued long-term potentiation from Aβ1-42-induced damage in the rat hippocampal CA1 region in vivo, and antagonized Aβ1-42-induced reduction of cyclic adenosine monophosphate and phosphorylated-cAMP response element-binding protein in rat hippocampal tissue using ELISA and western blot analysis, respectively. Thus, the results of the present study provide theoretical support for the application of Exendin-4 for improving AD.

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Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex

Cited by 33 publications

References 54 publications

Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor

Age-Related Decrease in Glucagon-Like Peptide-1 in Mouse Prefrontal Cortex but Not in Hippocampus Despite the Preservation of Its Receptor

Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice

Exendin-4 antagonizes Aβ1-42-induced attenuation of spatial learning and memory ability

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