INVESTIGADORES
SANZ BLASCO Sara Isabel
congresos y reuniones científicas
Título:
Role of astrocytic glutamatergic signaling in abeta oligomers toxicity
Autor/es:
SANZ BLASCO S; DZIEWCZAPOLSKI G; STOUFER DG; LEE B; WOLOSKER H; HEINEMANN SF; PARSONS LH; PINA CRESPO JC; LIPTON SA
Lugar:
Santiago de Compostela
Reunión:
Congreso; Joint FEPS and Spanish Physiological Society Scientific Congress 2012; 2012
Institución organizadora:
SECF
Resumen:
Objectives:
Recent failures of clinical
trials for Alzheimer's disease (AD) using anti-amyloid beta-peptide
(Abeta) approaches suggest that it may be necessary to attack downstream
targets in the Abeta cascade. To elucidate such targets, we studied the
effect of oligomerized Abeta on astrocytes. Astrocytes are known to
modulate neuronal excitability and synaptic transmission.
Here we
evaluate the effects of Abeta on intracellular Ca2+ and glutamate levels
in astrocytes in vitro, as well as in wild type mice (WT) and mice
expressing the human amyloid protein precursor (hAPPtg). First, we used
the glutamate sensing fluorescent reporter (SuperGluSnFR) developed by
Roger Tsien to perform sensitive optical measurements of glutamate
release in response to Abeta. Second, we performed microdialysis
measurements of glutamate levels in the hippocampues of WT and hAPPtg
mice.
Materials:
Glutamate release from astrocytes was
measured in vitro by FRET microscopy using SuperGluSnFR, for optical
measurement of glutamate. In vivo levels of extracellular glutamate were
analyzed using a combination of intracerebral microdialysis and liquid
chromatography?mass spectrometry (LC-MS).
Results:
Abeta
oligomers induced intracellular Ca2+ elevation and glutamate release
from astrocytes. In vivo, extracellular levels of glutamate were higher
in hAPPtg mice than in WT mice.
Conclusions:
Nanomolar
concentrations of oligomerized (but not non-oligomerized) Abeta induced
release of several tens of micromolar glutamate from cultured
astrocytes. These levels of glutamate can cause excitotoxic damage and
synaptic loss in neurons. In vivo measurements of the glutamate levels
in APP brains confirmed these results. Taken together with prior
studies, our work suggests that the neurotoxic effects of Abeta may be
mediated at least in part by local release of glutamate from astrocytes.
Our finding that oligomeric Abeta induces changes in intracellular Ca2+
levels and extracellular release of glutamate points to a role of
glutamatergic signaling in the pathogenesis of AD and the importance of
addressing excitotoxicity synaptic damage in the future treatment of AD.