Abstract
Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropathologies including Alzheimer's disease (AD). In the triple transgenic mouse model of AD (3xTg-AD) generalised hippocampal astroglia atrophy precedes a restricted and specific β-amyloid (Aβ) plaque-related astrogliosis. Astrocytes are critical for CNS glutamatergic transmission being the principal elements of glutamate homeostasis through maintaining its synthesis, uptake and turnover via glutamate-glutamine shuttle. Glutamine synthetase (GS), which is specifically expressed in astrocytes, forms glutamine by an ATP-dependent amination of glutamate. Here, we report changes in GS astrocytic expression in two major cognitive areas of the hippocampus (the dentate gyrus, DG and the CA1) in 3xTg-AD animals aged between 9 and 18 months. We found a significant reduction in Nv (number of cell/mm3) of GS immunoreactive (GS-IR) astrocytes starting from 12 months (28.59%) of age in the DG, and sustained at 18 months (31.65%). CA1 decrease of GS-positive astrocytes Nv (33.26%) occurs at 18 months. This Nv reduction of GS-IR astrocytes is paralleled by a decrease in overall GS expression (determined by its optical density) that becomes significant at 18 months (21.61% and 19.68% in DG and CA1, respectively). GS-IR Nv changes are directly associated with the presence of Aβ deposits showing a decrease of 47.92% as opposed to 23.47% in areas free of Aβ. These changes in GS containing astrocytes and GS-immunoreactivity indicate AD-related impairments of glutamate homeostatic system, at the advanced and late stages of the disease, which may affect the efficacy of glutamatergic transmission in the diseased brain that may contribute to the cognitive deficiency.
Highlights
The central nervous system relies on astrocytes for its correct functioning
Nv of glutamine synthetase (GS)-IR astrocytes decreases in Triple transgenic mouse of Alzheimer’s disease (3xTg-Alzheimer’s disease (AD)) mice From 12 months of age the 3xTg-AD mice showed a significant reduction of the Nv of GS immunoreactive (GS-IR) cells in the Dentate gyrus (DG) (4,852 ± 306 cells/mm3 vs 3,465 ± 344 cells/mm3; 28.59%, p = 0.016; Figure 3A) compared to the non-Tg control animals, whereas no apparent difference was found in Cornus ammonis 1 (CA1)
Our results in this animal model demonstrate that the expression of astroglial GS in hippocampus is affected at the human equivalent advanced and late stages of AD, as indicated by a reduction in both the Nv of GS-IR astrocytes and GS expression in the 3xTg-AD when compared to the control animals
Summary
The central nervous system relies on astrocytes for its correct functioning. Astroglia is critical for metabolic support to neurones by providing glucose and lactate [1,2], regulates ion environment, i.e. K+ and water movements and provides reactive-oxygen-species scavengers like glutathione [3,4,5].Astrocytes, as a component of the tripartite synapse, modulate neurotransmission and control the extracellular level of neurotransmitters [6,7,8,9,10,11]. Astrocytes are essential for glutamatergic transmission being key elements for “de novo“ synthesis of glutamate and for the glutamate-glutamine cycle; which, in addition, are fundamental for the synaptic plasticity associated to cognitive processes [12,13]. Astrocytic glutamine is transported back to neurones for its further conversion into glutamate [9,17]. The glutamate-glutamine shuttle makes both astrocytes and GS essential for glutamatergic neurotransmission [18]. At the same time astrocytic glutamate uptake prevents glutamate excitotoxicity [9]; disturbance of astroglial-based glutamate homeostasis may lead to neurotransmitter imbalance, neuronal malfunction and death, as well as impaired cognition [18,19]
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