MSpace at the University of Manitoba >
Faculty of Graduate Studies (Electronic Theses and Dissertations) >
FGS - Electronic Theses & Dissertations (Public) >
Please use this identifier to cite or link to this item:
|Title: ||Signaling pathways associated with Alzheimer’s disease and possible therapeutic targets|
|Authors: ||Schapansky, Jason|
|Supervisor: ||Glazner, Gordon (Pharmacology and Therapeutics)|
|Examining Committee: ||Anderson, Chris (Pharmacology and Therapeutics) Albensi, Benedict (Pharmacology and Therapeutics) Kong, Jiming (Human Anatomy and Cell Science)|
|Graduation Date: ||October 2011|
|Issue Date: ||3-May-2007|
NRC Research Press
|Abstract: ||Despite being first identified over a century ago, Alzheimer’s disease (AD) is a complex neurological disorder that still has not been properly characterized. Most cases are sporadic in nature, with an unidentifiable cause, but early-onset familial Alzheimer’s disease (FAD) is induced by genetic mutations in certain key genes. FAD mutations in the full length amyloid precursor protein (flAPP) increases production of the amyloid beta (Aβ) peptide responsible for plaque formation commonly associated with the disease, leading to neuronal death. A mutation in the PS1 gene (mPS1) results in increased APP cleavage into Aβ1-42, also leading to early AD formation. Although discoveries of FAD mutations have enabled concentrated studies into AD pathogenesis, its cause is still unknown.
In this thesis, experimental projects were designed to study how signaling pathways associated with markers of AD, including APP and PS1 gene mutations, could result in neuronal dysfunction associated with disease pathology, and how these pathways could be manipulated for use as potential therapeutic targets. Cortical neurons isolated from FAD mPS1 mice (expressing the Met146Val mPS1 protein) were analyzed to establish neuronal viability in response to Aβ1-42 insult compared to healthy neurons. mPS1 neurons were no more susceptible to cell death compared to wild-type neurons, because of an increased activation of the transcription factor nuclear factor kappa B (NF-κB) protein brought about by elevated endoplasmic reticulum (ER) calcium release due to the PS1 mutation. However, NF-κB inhibition in the mPS1 neurons caused increased pro-apoptotic protein CHOP expression leading to significantly higher cell death versus controls when neurons were exposed to Aβ1-42. Following this study, the role of the neurotrophic protein neuregulin on cytoplasmic calcium levels of hippocampal neurons was examined, with the intent of assessing the contributioin of that signaling pathway to AD neuropathology in AD transgenic mice. Neuregulin has been shown to modify glutamatergic channels at neuronal synapses, but how this could affect cytoplasmic calcium levels in neurons was uncertain. Long term treatment (24 hours), but not short-term (1 hr), with neuregulin increased glutamatergic-induced intracellular calcium levels in hippocampal neurons, through a PI3K-mediated mechanism. This study demonstrated that inhibition of the NRG/ErbB axis could be a possible therapeutic target to reduce excitotoxic levels of calcium leading to neuronal death in AD, or enhance synaptic plasticity and memory in AD-initiated areas of deficit. Finally, interactions between the neurotrophic insulin pathway and amyloid peptides were studied using an amyloid precursor protein (APP) overexpressing mouse model, the TgCRND8 strain. Despite insulin depletion induced by streptozotocin injection, young diabetic TgCRND8 mice displayed no impairment in insulin signaling compared to controls, likely due to activation of the insulin signaling pathway by sAPPα. This indicates a possible biological role for sAPPα that prevents diabetic-induced insulin signaling impairment. Thus, the data from these three projects elucidated different components of AD pathogenesis and possibly targets of future AD treatment.|
|Appears in Collections:||FGS - Electronic Theses & Dissertations (Public)|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.