Astrocytes and Glutamate Homoeostasis in Alzheimer's Disease: A Decrease in Glutamine Synthetase, But Not in Glutamate Transporter-1, in the Prefrontal Cortex

Author:

Kulijewicz-Nawrot Magdalena1,Syková Eva12,Chvátal Alexander1,Verkhratsky Alexei345,Rodríguez José J.45

Affiliation:

1. Institute of Experimental Medicine, ASCR, Videnska 1083, 142 20 Prague, Czech Republic

2. Department of Neuroscience and Center for Cell Therapy and Tissue Repair, Charles University, Second Medical Faculty, Prague, Czech Republic

3. Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, U.K.

4. IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain

5. Department of Neurosciences, University of the Basque Country UPV/EHU, 48940 Leioa, Spain and CIBERNED

Abstract

Astrocytes control tissue equilibrium and hence define the homoeostasis and function of the CNS (central nervous system). Being principal homoeostatic cells, astroglia are fundamental for various forms of neuropathology, including AD (Alzheimer's disease). AD is a progressive neurodegenerative disorder characterized by the loss of cognitive functions due to specific lesions in mnesic-associated regions, including the mPFC (medial prefrontal cortex). Here, we analyzed the expression of GS (glutamine synthetase) and GLT-1 (glutamate transporter-1) in astrocytes in the mPFC during the progression of AD in a triple-transgenic mouse model (3xTg-AD). GS is an astrocyte-specific enzyme, responsible for the intracellular conversion of glutamate into glutamine, whereas the removal of glutamate from the extracellular space is accomplished mainly by astroglia-specific GLT-1. We found a significant decrease in the numerical density (Nv, cells/mm3) of GS-positive astrocytes from early to middle ages (1–9 months; at the age of 1 month by 17%, 6 months by 27% and 9 months by 27% when compared with control animals) in parallel with a reduced expression of GS (determined by Western blots), which started at the age of 6 months and was sustained up to 12 months of age. We did not, however, find any changes in the expression of GLT-1, which implies an intact glutamate uptake mechanism. Our results indicate that the decrease in GS expression may underlie a gradual decline in the vital astrocyte-dependent glutamate–glutamine conversion pathway, which in turn may compromise glutamate homoeostasis, leading towards failures in synaptic connectivity with deficient cognition and memory.

Publisher

SAGE Publications

Subject

Neurology (clinical),General Neuroscience

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