Aberrant Expression of the Glutamate Transporter Excitatory Amino Acid Transporter 1 (EAAT1) in Alzheimer's Disease

Abstract

Glutamate-mediated toxicity has been implicated in the neurodegeneration observed in Alzheimer's disease. In particular, glutamate transport dysfunction may increase susceptibility to glutamate toxicity, thereby contributing to neuronal cell injury and death. In this study, we examined the cellular localization of the glial glutamate transporter excitatory amino acid transporter 1 (EAAT1) in the cerebral cortex of control, Alzheimer's disease, and non-Alzheimer dementia cases. We found that EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology.In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1. These findings suggest that EAAT1 changes are related to tau expression (and hence neurofibrillary tangle formation) in dementia cases showing Alzheimer-type pathology. This study implicates aberrant glutamate transporter expression as a mechanism involved in neurodegeneration in Alzheimer's disease.

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease

“…5), although no correlation was observed with MMSE. It is remarkable that in AD patients not only EAAT2 [55] but also EAAT1 [49] display an aberrant expression in neurons, indicating an important role also for this latter glutamate transporter in AD. These data support the hypothesis that abnormalities in glutamate transport play an important role in the pathogenesis of AD.…”

“…Moreover, reduced expression of GLT1 (EAAT2) in global transient ischemia animal model [56] and in ALS patients [30,47] seems responsible for the elevation of extracellular glutamate concentration and neuronal death. Molecular and/or functional characterizations of glutamate transporters were performed in different cell culture models from CNS and peripheral tissues, in order to investigate the regulation of their expression, translocation and activity by various endogenous and exogenous factors [11][12][13]21,35,38,49].…”

Astroglial calcium signalling in Alzheimer's disease

“…In particular β-amyloid binds to and modulates Ca 2+ -permeable neuronal acetylcholine receptors in α7 (homomeric), α7β2 and α4β2 compositions; β-amyloid activates α7 receptors in picomolar concentrations, while inhibits the both of above heteromeric receptors in nanomolar concentrations [14,15]. There are certain arguments that β-amyloid excitotoxicity is mediated by extra-synaptic NMDA receptors [16], although this might be an indirect effect (for example, through an inhibition of astroglial glutamate clearance systems [17]). Polymorphism of the encoding gene of the recently identified Ca 2+ homeostasis modulator 1 channel (CALHM1), which is present in neuronal plasmalemma and endomembranes [18,19], has been associated with some forms of AD [20]; the aberrant form of CALHM1 arguably deregulated neuronal Ca 2+ homeostasis [21,22].…”

Variations in Promoter Activity Reveal a Differential Expression and Physiology of Glutamate Transporters by Glia in the Developing and Mature CNS

“…GLAST, the embryonically dominant transporter, has its expression restricted in the adult. GLAST is also altered in neurological and psychiatric diseases (Banner et al, 2002;Scott et al, 2002). Understanding the regional and cellular regulation of these synaptically relevant genes is significant from a pathogenic and therapeutic perspective.…”