title: Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer's Disease.
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.
authors.affiliation: Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System (VAPSHCS), Seattle, WA, USA.
authors.forename: Kole D
authors.initials: KD
authors.lastname: Meeker
authors.affiliation: Mental Illness Research, Education, and Clinical Center (MIRECC), Veterans Affairs Puget Sound Health Care System (VAPSHCS), Seattle, WA, USA Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.affiliation: Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System (VAPSHCS), Seattle, WA, USA Division of Gerontology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D027342:Excitatory Amino Acid Transporter 2; D007328:Insulin; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051058:Oncogene Protein v-akt
keywords: Amyloid-β; EAAT2; GLT1; SLC1A2; excitotoxicity; metabolism