The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer's disease

Tsai, Wang Wei Vicky. (2005). The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer's disease PhD Thesis, School of Molecular and Microbial Sciences, The University of Queensland.

       
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Author Tsai, Wang Wei Vicky.
Thesis Title The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer's disease
School, Centre or Institute School of Molecular and Microbial Sciences
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor Dodd, P.
Total pages 203
Collection year 2005
Language eng
Subjects L
270107 Cell Neurochemistry
780105 Biological sciences
Formatted abstract

Neurodegenerative diseases such as Huntington's disease, ischaemia, and Alzheimer's disease (AD) are major causes of death in the world. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-protein, have become of interest for many studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3), calcium ions and cAMP. Group I mGluRs cause the release of arachidonic acid by intracellular Ca2+ mobilization, which facilitates the release of glutamate and triggers the accumulation of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease. Further, mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. mGluRs may also play a role in glutamate-induced neuronal death, by facilitating the release of Ca2+ from intracellular stores such as mitochondria and endoplasmic reticulum. Hence, mGluRs have become a potential pharmacological target for neuroprotective drug development. They represent a pharmacological path for producing a relatively subtle modulation of glutamate systems in the CNS when compared with other approaches, because they serve a modulatory rather than a direct role in excitatory glutamatergic synaptic transmission. 

 

In this study, the aims were to determine regional mGluR-1α and mGluR-5 levels and distributions in healthy human controls and AD cases; and to search for potential ligands for this group I mGluRs. Immunohistochemistry, performed using mGluR-1α and mGluR-5 polyclonal antibodies on paraformaldehyde-fixed tissue sections, showed that mGluR-1α immunoreactivity was concentrated in the stratum lucidum and molecular layer of CA1 in both control and AD hippocampus, whereas abundant mGluR5 immunoreactivity was found in pyramidal cells and the pleomorphic cell layer of the dentate gyrus in AD hippocampus cf. weak labeling in controls. No mGluR-1α immunoreactivity was found in either control or AD occipital cortex. 

 

Strong mGluR5 signals were detected in control occipital cortex. In contrast, predominant mGluR5 staining was observed in AD mid-temporal cortex. Western-blot and [3H]quisqualate specific-binding assays were also used to define the mGluR-1α and mGluR-5 receptor profiles. Relative protein expression studies showed that mGluR-5 was expressed prominently in hippocampus, an AD-affected region. [3H]QA receptor binding profile suggested that significantly higher QA binding site was detected in AD hippocampus and superior temporal cortex. The binding affinity of QA to AD hippocampus was significantly higher than other regions examined. Radioligand binding assay was used to screen venoms extracted from Conus snails as potential ligands. A low-MW active compound was detected. We also evaluated the effects of Ala-7-conantokin-G (Con-GA7) and ifenprodil on the modulation by spermine of [3H]MK801 binding to human cortical membranes. Human cortical tissue was obtained at autopsy and stored at -80°C until assay. Both Con-GA7 and ifenprodil inhibited [3H]MK801 binding, but spermine affected these inhibitions differently. Con-GA7 IC50 changed little with spermine concentration, indicative of a non-competitive interaction, whereas the rightward shift in ifenprodil IC50 with increasing spermine concentration suggested partial competition. When the two agents were tested against the biphasic activation of [3H]MK801 binding by spermine, they again differed in their effects. In the activation phase Con-GA7 was a non-competitive inhibitor of spermine activation, and may even enhance the spermine EC50, while the ifenprodil data indicated a partially competitive interaction. Both agents were non-competitive in the inhibitory phase. Overall, the data suggest that Con-GA7 and ifenprodil interact differently with the polyamine modulation of the glutamate-NMDA receptor. 

Keyword Alzheimer's disease
Glutamic acid

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
 
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Created: Fri, 24 Aug 2007, 18:46:58 EST