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.

Current approaches to enhance glutamate transporter function and expression

“…Recently, a study revealed that GLT‐1 loss also caused an apparent compensatory increase in insulin‐degrading enzyme activity in the liver, an organ that has been shown to regulate peripheral aβ levels and expresses GLT‐1, suggesting that partial GLT‐1 loss can cause insulin/Akt (protein kinase B) signaling abnormalities observed in AD (Meeker et al . ).…”

Mechanism of 2,3,4',5-Tetrahydroxystilbene 2-O-β-<smlcap>D</smlcap>-Glucoside-Induced Upregulation of Glutamate Transporter 1 Protein Expression in Mouse Primary Astrocytes

“…But how TSG exactly exerts neuronal protective effects remains obscure. It is well known that the injury of neurons in CNS disorders, such as Alzheimer's disease and brain ischemia, can be mediated by the impairment of astrocytic glutamate transporters [18,19]. In brain ischemia, the impairment astrocytic glutamate transporters would induce the over-accumulation of extracellular glutamate and then lead to the over-activation of glutamate receptors [20].…”

The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy

“…This leads to an increase in glutamate concentration at the synaptic cleft triggering excitotoxicity mediated neurodegeneration [ 80 , 82 ]. Nonetheless, loss of EAAT2 function increases the activity of insulin-degrading enzymes in the liver, suggesting that the loss of EAATs causes insulin/protein kinase B signaling abnormalities in AD [ 83 ]. These findings suggest that EAAT2 loss/dysfunction associated with AD pathology and EAAT2 could be used as a therapeutic target for neuroprotection in glutamate-mediated excitotoxicity.…”