Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease

Abstract

The intracellular localization of glutamine synthetase (GS) in the inferior temporal cortices of non-demented elderly individuals was compared with that in brains affected by Alzheimer's disease (AD). The present study confirmed previous reports of a general decrease in GS expression in astrocytes and the expression of GS in some neurons. Several new observations were made: the morphology of astrocytes is generally unaffected by the presence of plaques, GS labeling is present in some diffuse plaques and occasional neuritic plaques, whereas the overall density of astrocytes increases 1.4-fold in AD. In addition, the present study found that the reduction in GS expression is almost entirely due to a loss of GS from perisynaptic regions of the neuropil and from the astrocytic endfeet that normally abut cortical blood vessels. These changes implicate astrocytes in glutamate excitotoxicity and ammonia neurotoxicity. It is suggested that it may be more fruitful to regard AD not as a neuronal disease, but as a disorder of astrocyte-neuron interactions.

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…133 Third, mGluR 5 activation has also been shown to increase STEP 61 translation in rat hippocampal slices and synaptosomes, which leads to extracellular signal-related kinase1/2 (ERK1/2)-dependent dephosphorylation of the GluR2 isoform and subsequent endocytosis of the AMPA receptor. 136 Taken together these findings indicate that amyloid β can activate and increase protein levels of STEP 61 , resulting in enhanced dephosporylation and endocytosis of glutamate receptors and reduced synaptic function.…”

“…72 Changes in glutamate transporter expression have been identified at an early stage of Alzheimer disease, indicating that dysfunction in glutamate transport might be an early event in the disease pathology. 71 Concurrent with reduced glutamate transporters there is a reduction in glutamine synthetase in Alzheimer disease, 61 thus preventing the transport of glutamate back to presynaptic neur ons. High levels of glutamate in astrocytes lead to the risk of glutamate being returned to the synaptic cleft if mitochon drial membranes are depolarized, a process that is thought to occur in Alzheimer disease because of reduced energy supplies.…”

“…Exogenous application of amyloid β1-42 to nontransgenic cortical neurons promoted NMDA receptor endocytosis, indicating that the reduced receptor levels at the cell surface of APP sw mice was due to increased removal rather than disrupted trafficking to the membrane. 133 A role for striatal-enriched tyrosine phosphatase (STEP 61 ) has recently been linked to amyloid β-induced synaptic function since it increases the endocytosis of NMDA and AMPA receptors from the postsynaptic membrane. [133][134][135][136] The STEP 61 is enriched in synapses, suggesting that it has a specialized role in cell signalling.…”

“…[133][134][135][136] The STEP 61 is enriched in synapses, suggesting that it has a specialized role in cell signalling. The levels of STEP 61 were reported to be increased in 2 mouse models of Alzheimer disease 133 and in humans 135 with Alzheimer disease. There is evidence that amyloid β peptides, delivered using the enriched conditioned media of cells overexpressing APP, can increase synaptic depression by enhancing STEP 61 activity via multiple mechanisms.…”

Synaptic protein expression is regulated by a pro-oxidant diet in APPxPS1 mice

“…Immunohistological studies suggest that there is a reduction in the expression of GS in AD brain (Robinson 2000(Robinson , 2001. In rat cortical cultures, however, aggregated Ab 1-42 peptide stimulated the expression of GS (Pike et al 1996).…”