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

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.

“Targeting astrocytes in CNS injury and disease: A translational research approach”

“…Conversely, expression of glutamine synthase was reduced over time, leading to a gradual decline in astrocyte-dependent glutamate homeostasis. This disruption in glutamate levels results in failed synaptic connectivity and ultimately cognitive and memory deficits (Kulijewicz-Nawrot et al, 2013). Calcium homeostasis in reactive astrocytes may also be altered in AD.…”

Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

“…Additionally, the distribution of the GS expression in the cerebral cortex is perturbed, and may be triggered by toxic agents in senile plaques, reduced noradrenergic supply to the cerebral cortex, and increased brain ammonia levels [102]. The resulting secondary GS deficiency progressively leads to incomplete ammonia detoxification and a gradual decline of the glutamine-glutamate-GABA cycle, causing impairment in synaptic connectivity with deficient cognition and memory [102,105]. …”

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

“…Although the pathogenesis of AD is still elusive, there is ample consensus that the abnormal Aβ deposition in the central nervous system (CNS) plays a crucial role, especially the Aβ 1–42 in the form of soluble oligomers (Tam and Pasternak 2012). Additionally, disturbances in insulin signaling and abnormalities of the glutamate neurotransmitter system are also involved in AD (On 2013a; Kulijewicz-Nawrot et al 2013). …”