Characterisation of a novel p75 neurotrophin receptor death signalling pathway

Linda May (2011). Characterisation of a novel p75 neurotrophin receptor death signalling pathway PhD Thesis, Queensland Brain Institute, The University of Queensland.

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Author Linda May
Thesis Title Characterisation of a novel p75 neurotrophin receptor death signalling pathway
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2011-10
Thesis type PhD Thesis
Supervisor Associate Professor Elizabeth Coulson
Professor Pankaj Sah
Total pages 192
Total colour pages 19
Total black and white pages 173
Language eng
Subjects 110902 Cellular Nervous System
060103 Cell Development, Proliferation and Death
Abstract/Summary The Alzheimer’s disease (AD) peptide amyloid beta1-42 (Aβ42) has been shown to initiate death signalling through the p75 neurotrophin receptor (p75NTR), however little is known about the Aβ42-p75NTR mechanism of cell death or how such a mechanism would fit with what is known about amyloid pathology. Using a combination of in vitro and in vivo techniques, we demonstrate here that Aβ42 has excitatory properties which promote an increase in intracellular levels of calcium in neurons, which in turn causes an increase in G-protein activated inwardly rectifying potassium (GIRK) channels at the plasma membrane. p75NTR activates these GIRK channels to cause a sustained potassium efflux which leads to caspase activation and cell death. We found that the NMDA receptor is involved in the Aβ42-initiated calcium overload in neurons, which drives the GIRK channel response. Further, chronic activation of the inhibitory GABAb receptor removes GIRK channels from the surface of the neuron and overrides neuronal death in vitro. We also show that GIRK channels are upregulated in response to excitotoxic insults in scenarios where p75NTR death signalling occurs. GIRK channels are increased in vivo in the dentate region of the hippocampus after pilocarpine-induced seizures in mice, and in vitro in hippocampal neurons where excessive glutamate challenge potentiates p75NTR-dependent death signalling. We found that p75NTR expression in the mouse hippocampus is increased in vivo due to normal ageing and further increased in a transgenic mouse model of AD and in human AD post-mortem tissue. Finally, we report that in human post-mortem tissue, the levels of SDS-soluble Aβ42, p75NTR and GIRK proteins together accurately predicted clinically diagnosed cases of AD. Conclusion: Our results demonstrate that Aβ42 activates p75NTR and upregulates GIRK channels which activated p75NTR uses to cause potassium efflux and cell death. By precipitating cellular dysregulation of calcium and subsequent inhibitory responses, Aβ42 provides both the impetus and the means for p75NTR death signalling. The p75NTR-GIRK channel death mechanism may provide a paradigm for understanding other forms of excitotoxic neurodegeneration.
Keyword p75NTR, GIRK, Aβ42, excitotoxicity, Alzheimer's disease, GABAb receptor
Additional Notes 22,30,33,65,67,74,80,81,110,118,124,127,128,132,139,142,146, 148,156

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Created: Mon, 30 Apr 2012, 21:32:30 EST by Linda May on behalf of Library - Information Access Service