β-Amyloid Enhances Glial Glutamate Uptake Activity and Attenuates Synaptic Efficacy

Abstract

Although amyloid ␤-protein (A␤) has long been implicated in the pathogenesis of Alzheimer's disease, little is known about the mechanism by which A␤ causes dementia. A␤ leads to neuronal cell death in vivo and in vitro, but recent evidence suggests that the property of the amnesic characteristic of Alzheimer's disease can be explained by a malfunction of synapses rather than a loss of neurons. Here we show that prolonged treatment with A␤ augments the glutamate clearance ability of cultured astrocytes and induces a dramatic decrease in glutamatergic synaptic activity of neurons cocultured with the astrocytes. Biotinylation assay revealed that the enhancement of glutamate uptake activity was associated with an increase in cell-surface expression of GLAST, a subtype of glial glutamate transporters, without apparent changes in the total amount of GLAST. This phenomenon was blocked efficiently by actindisrupting agents. Thus, A␤-induced actin-dependent GLAST redistribution and relevant synaptic malfunction may be a cellular basis for the amnesia of Alzheimer's disease.Amyloid ␤-protein (A␤), 1 a peptide with 40 -42 residues, is a main element of senile plaque, a hallmark of Alzheimer's disease (AD) (1, 2), and is accumulated highly in the forebrain of AD patients, as well as transgenic mice overexpressing mutant ␤-amyloid precursor protein (␤APP), which develop AD-like pathology (3, 4). Although numerous studies showed that exogenously applied or endogenously produced A␤ leads to neuronal cell death, the amnesic feature of AD cannot be explained by the neuronal loss alone (5). Indeed, accumulating evidence indicates that A␤ induces severe impairment of excitatory neurotransmission in the hippocampus (6 -8) and thereby may cause memory deficits (9). In mutant ␤APP transgenic mice, such synaptic malfunction often appears in advance of A␤ plaque formation (10, 11), and cognitive deterioration is also observed without apparent neurodegeneration (4, 12). A␤-induced synaptic deterioration rather than neuronal loss is, therefore, likely to be a main cause of early AD dementia (5, 13). However, the mechanisms by which A␤ causes such synaptic malfunction remain to be elucidated.Excitatory neurotransmission is tightly regulated by a rapid clearance of the neurotransmitter glutamate from the extracellular milieu through Na ϩ -dependent L-glutamate transporters that are expressed on astrocytes, i.e. GLAST and GLT-1 (14, 15). We therefore investigated the effect of A␤ on glutamate uptake activity in cultured cortical astrocytes. Here we show for the first time that A␤ ending at 42 residues (A␤ (1-42)) induces an increase in the activity of GLAST. This work further demonstrates that A␤ (1-42) stimulates actin-dependent GLAST redistribution from subcellular compartment to the cell surface. Such up-regulation of GLAST function may attenuate glutamatergic synaptic efficacy. EXPERIMENTAL PROCEDURESMaterials-Chemically synthesized A␤ (1-40) and A␤ (1-42) were gifts from Dr. T. Shirasawa (Department of Molecular Genetics, Tokyo Metropo...

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…Our results show early changes in the absence of significant Purkinje cell pathology. The expression and spatial distribution of EAAT1, a glial glutamate transporter (Danbolt, 2001) with key roles in neuron-glia interaction (Watanabe, 2002) and in other neurodegenerative diseases (Ikegaya et al, 2002), is disarranged in our study, presenting with a cluster-like appearance in DTg mice. This finding indicates a that there is a change in glutamate signaling, which is in accordance with microarray studies that report alteration of the expression of genes that encode proteins involved in glutamate signaling pathways in Purkinje cells (Serra et al, 2004).…”

Regional Distribution of Sodium-Dependent Excitatory Amino Acid Transporters in Rat Spinal Cord

“…The measure scheme for the dorsal horn depicted in Figure 1, which included Rexed laminae I, II, III, and portions of IV (40,41), could mask significant differences in quantitative densities if measures had been taken in individual laminae. However, absolute densities of EAATs in the rat cord are approximately 10-fold lower than binding density in many brain regions (19), which implies a lower capacity to clear glutamate in spinal cord, assuming the majority of EAATs are plasma membrane bound (53)(54)(55)(56). Although unlikely because of the time course involved, it cannot be ruled out that Na þ -dependent binding density was altered by decapitation.…”

Aβ(25–35)-Induced Memory Impairment, Axonal Atrophy, and Synaptic Loss are Ameliorated by M1, A Metabolite of Protopanaxadiol-Type Saponins

“…Oligomers of Ab, and not monomers or fibrils, are primarily involved in the inhibition of in vivo LTP in rats (Walsh et al, 2002) and in the memory dysfunction of APPtransgenic mice Tg2576 (Kotilinek et al, 2002). Spontaneous excitatory postsynaptic currents in cultured hippocampal neurons have been found to be reduced in the Ab(1-40) and Ab(1-42) groups only 12 h after treatment (Ikegaya et al, 2002). These findings suggest that synaptic loss begins at a relatively early phase in AD patients, and that high fibrilization of Ab does not appear to be critical to memory loss (Yamada and Nabeshima, 2000).…”