Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.631252
Title: The amyloid precursor protein and the axonal transport of mitochondria in Alzheimer's disease
Author: Gibbons-Frendo, Sam
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2012
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Abstract:
Defects in axonal transport are an early pathological event in Alzheimer’s disease, suggesting that damage to the transport process could contribute to the disease. A large number of cargoes are transported through axons and mitochondria represent a particularly important cargo. This is because mitochondria need to be distributed to axonal regions where their functions in ATP synthesis and the regulation of calcium homeostasis are required. This is particularly important in synaptic regions where neurons have high energy and calcium-buffering requirements. As such, mitochondria are transported bi-directionally through axons and this movement is responsive to physiological stimuli. has been shown to disrupt axonal transport of mitochondria but these studies involved application of synthetic Ap to neuronal culture media. In this thesis, the effect of the expression of a familial Alzheimer’s disease mutant amyloid precursor protein (APP) that increases Ap production (the APP Swedish mutant) on axonal transport of mitochondria was studied. This approach represents a more physiological route for studying the effect of APP and Ap on axonal transport. Mitochondrial axonal transport was monitored in cultured neurons via time-lapse microscopy. Expression of APPswe led to a selective disruption of anterograde but not retrograde axonal transport of mitochondria. Mitochondria are transported anterogradely on the microtubule based molecular motor kinesin-1. Mitochondria attach to kinesin-1 via the outer mitochondrial membrane protein Mirol and the adaptor protein TRAK1. Defective mitochondrial transport induced by APPswe did not affect the binding of kinesin-1 to mitochondria. Rather, APPswe caused mitochondria with associated Mirol, TRAKl and kinesin-1 to detach from the microtubule rails. In order to gain insight into the molecular mechanisms that underlie the APPswe effect on transport and to test potential therapeutic approaches, a number of different Alzheimer’s disease-associated features were experimentally manipulated. In particular, inhibition of APP processing and A|3 production with the y-secretase inhibitor DAPT, inhibition of glycogen synthase kinase-3 and increased tubulin acetylation all rescued the APPswe-induced transport defect. These results provide novel insight into the mechanisms underlying defective axonal transport in Alzheimer’s disease and provide new information on how some proposed Alzheimer’s disease therapeutics might act at a molecular level.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.631252  DOI: Not available
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