Beta-amyloid enhances glial glutamate uptake activity and attenuates synaptic efficacy.
Although amyloid beta-protein (A beta) has long been implicated in the pathogenesis of Alzheimer's disease, little is known about the mechanism by which A beta causes dementia. A beta 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 beta 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 actin-disrupting agents. Thus, A beta-induced actin-dependent GLAST redistribution and relevant synaptic malfunction may be a cellular basis for the amnesia of Alzheimer's disease.
Ikegaya
Yuji
Y
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. ikegaya@tk.airnet.ne.jp
Matsuura
Sigeru
S
Ueno
Sayaka
S
Baba
Atsushi
A
Yamada
Maki K
MK
Nishiyama
Nobuyoshi
N
Matsuki
Norio
N
D027322:Amino Acid Transport System X-AG / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D019921:Biotinylation; D002478:Cells, Cultured; D002540:Cerebral Cortex; D018698:Glutamic Acid / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; C011274:3-hydroxyaspartic acid; D001224:Aspartic Acid; D018698:Glutamic Acid