ArticleJournal of Alzheimer's disease : JAD2015
Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer's Disease.
Article in Journal of Alzheimer's disease : JAD, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Impairment of hippocampal long-term potentiation by soluble amyloid-β oligomers is mediated by glutamate transporter 1 expressed in neurons.Neural regeneration research · 2026Article
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- Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities.Molecular psychiatry · 2022Review
- Activation of the TREK-1 Potassium Channel Improved Cognitive Deficits in a Mouse Model of Alzheimer's Disease by Modulating Glutamate Metabolism.Molecular neurobiology · 2022Article
- Control of complex behavior by astrocytes and microglia.Neuroscience and biobehavioral reviews · 2022Review
- Evaluation of Utilizing the Distinct Genes as Predictive Biomarkers in Late-Onset Alzheimer's Disease.Global medical genetics · 2022Article
- Article
- Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes.PLoS computational biology · 2022Article
- Epileptic Mechanisms Shared by Alzheimer's Disease: Viewed via the Unique Lens of Genetic Epilepsy.International journal of molecular sciences · 2021Review
- Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer's disease.Ageing research reviews · 2021Review
- The Dual Role of Glutamatergic Neurotransmission in Alzheimer's Disease: From Pathophysiology to Pharmacotherapy.International journal of molecular sciences · 2020Review
- Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Glutamate transporters: The arrestin connection.Oncotarget · 2017Article
- The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2016Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The glutamate transporter GLT-1 (also called EAAT2 in humans) plays a critical role in regulating extracellular glutamate levels in the central nervous system (CNS). In Alzheimer's disease (AD), EAAT2 loss is associated with neuropathology and cognitive impairment. In keeping with this, we have reported that partial GLT-1 loss (GLT-1+/-) causes early-occurring cognitive deficits in mice harboring familial AD AβPPswe/PS1ΔE9 mutations. GLT-1 plays important roles in several molecular pathways that regulate brain metabolism, including Akt and insulin signaling in astrocytes. Significantly, AD pathogenesis also involves chronic Akt activation and reduced insulin signaling in the CNS. In this report we tested the hypothesis that GLT-1 heterozygosity (which reduces GLT-1 to levels that are comparable to losses in AD patients) in AβPPswe/PS1ΔE9 mice would induce sustained activation of Akt and disturb components of the CNS insulin signaling cascade. We found that partial GLT-1 loss chronically increased Akt activation (reflected by increased phosphorylation at serine 473), impaired insulin signaling (reflected by decreased IRβ phosphorylation of tyrosines 1150/1151 and increased IRS-1 phosphorylation at serines 632/635 - denoted as 636/639 in humans), and reduced insulin degrading enzyme (IDE) activity in brains of mice expressing familial AβPPswe/PS1ΔE9 AD mutations. GLT-1 loss also caused an apparent compensatory increase in IDE activity in the liver, an organ that has been shown to regulate peripheral amyloid-β levels and expresses GLT-1. Taken together, these findings demonstrate that partial GLT-1 loss can cause insulin/Akt signaling abnormalities that are in keeping with those observed in AD.
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