Modulators of calcium signalling in neuronal physiology and disease
Abstract
This thesis focuses on the regulation of the ubiquitous second messenger Ca2+ in neuronal physiology and disease. Ca2+ signalling in neurons is regulated by ion channels located in the plasma membrane, as well as in the endoplasmic reticulum (ER) and mitochondrial membranes. Ca2+ signalling is essential for numerous cellular processes, including neuronal excitability, neurotransmitter release, synaptic plasticity, and induction of cell death. Age-related disruptions in Ca2+ signalling may contribute to decline of cognitive function and motor control associated with aging. Furthermore, disruption in neuronal Ca2+ signalling is implicated in several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). In this thesis, I studied neuronal Ca signalling and how it is affected in neurodegenerative disease. First, I examined the role of the ER Ca2+ binding protein Calreticulin (CRT) in AD. CRT is involved in regulation of ER Ca signalling and modulation of susceptibility to cell death. I found that there was an increase in the expression of CRT in in vitro and in vivo models of AD. However, increased levels of CRT did not alter susceptibility of neuronal cells to death induced by AD-related stressors. Second, I examined the role of X-Linked Inhibitor of Apoptosis Protein (XIAP) in the modulation of neuronal Ca2+ signalling. I found that overexpression of XIAP in neuronal cells modified Ca signalling by decreasing Ca2+ flux through multiple plasma membrane and ER channels. These effects appear to be independent of caspase inhibition, which is one of the ways that XIAP can inhibit apoptosis. Third, I examined a compound found in green tea, L-theanine, a i glutamate receptor antagonist that is protective in models of excitotoxic neuronal injury.
I found that 24 hour L-theanine treatment reduces the amount of Ca2+ released from neuronal intracellular stores in response to both glutamate stimulation and passive leak through ER channels. An acute 30 minute L-theanine treatment had similar effects. In conclusion, these observations further the understanding of the regulation of Ca2+ signalling in neurons and may lead to novel therapeutic strategies in neurodegenerative disease.
http://udini.proquest.com/view/modulators-of-calcium-signalling-in-goid:304406903/
L-theanine, an amino acid in green tea, attenuated beta-amyloid-induced cognitive dysfunction and neurotoxicity: Reduction of oxidative damages and inactivation of ERK/p38 kinase and NF-kappaB pathways.
Abstract
Amyloid beta (Abeta)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). In this study, we investigated the inhibitory effect of L-theanine, a component of green tea (Camellia sinensis), on Abeta(1-42)-induced neuronal cell death and memory impairment.
Oral treatment of L-theanine (2 and 4 mg/kg) in drinking water for 5 weeks in mice, followed by injection of Abeta(1-42) (2 mug/mouse, i.c.v.) significantly attenuated Abeta(1-42)-induced memory impairment.
Furthermore, L-theanine reduced Abeta(1-42) levels accompanied with the Abeta(1-42)-induced neuronal cell death in cortex and hippocampus of the brain.
Moreover, L-theanine inhibited Abeta(1-42)-induced extracellular signal-regulated kinase (ERK) and p38 mitogenic activated protein kinase (p38 MAPK) as well as the activity of nuclear factor kappa-B (NF-kappaB).
L-theanine also significantly reduced oxidative protein and lipid damage, and elevation of glutathione level in the brain. These data suggest that the positive effects of L-theanine on memory may be mediated by suppression of ERK/p38 and NF-kappaB as well as the reduction of macromolecular oxidative damage. Thus, L-theanine may be useful in the prevention and treatment of AD.
www.citeulike.org/group/5070/article/5812982L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway.
stract
As a natural analogue of glutamate, l-theanine is the unique amino acid derivative in green tea. Although its underlining mechanisms are not yet clear, it has been suggested that l-theanine treatment may prove beneficial to patients with neurodegenerative diseases.
In this study, we investigated the neuroprotective effect and its mechanism of l-theanine in an in vitro model of Alzheimer's disease by using the human APP (Swedish mutation) transgenic SH-SY5Y cell.
Amyloid beta (Abeta) neurotoxicity was triggered by l-glutamate in this cell line.
Additionally, l-theanine significantly attenuated l-glutamate-induced apoptosis at similar levels to those seen with the NMDA receptor inhibitor MK-801 in the stably expressing APP Swedish mutation SH-SY5Y cells which over-generated Abeta.
Meanwhile, the activation of c-Jun N-terminal kinase and caspase-3 induced by l-glutamate was suppressed by l-theanine.
We also found that cells treated with l-theanine showed decreased production of nitric oxide resulting from the down-regulated protein levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS).
These results indicate that the inhibition of the NMDA subtype of glutamate receptors and its related pathways is the crucial point of the neuroprotective effect of l-theanine in the cell model.
Thus, our present study supports the notion that l-theanine may provide effective prophylaxis and treatment for Alzheimer's disease.
http://www.researchgate.net/publication/43340817_L-theanine_protects_the_APP_(Swedish_mutation)_transgenic_SH-SY5Y_cell_against_glutamate-induced_excitotoxicity_via_inhibition_of_the_NMDA_receptor_pathway
Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again