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Investigating the potential of therapeutically targeting the Insulin and Insulin-like Signalling Cascade in neurodegeneration

Paulin, JJW; (2017) Investigating the potential of therapeutically targeting the Insulin and Insulin-like Signalling Cascade in neurodegeneration. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Decreasing signalling through the Insulin and Insulin-like Signalling (IIS) cascade by genetic and pharmacological means can increase the lifespan and healthspan of many organisms. Crucially, when long-lived animals are crossed with animal models of neurodegenerative disorders, the onset of pathology is slowed. Pharmacological inhibitors of the IIS cascade have also shown neurodegeneration delaying and neuroprotective properties. Furthermore, IIS is changed in neurodegenerative disorders; with increased astrocyte IGF1, localised increased ERK1/2 phosphorylation (p-ERK), and brain insulin and IGF1 resistance observed. The IIS cascade therefore seems critically implicated in neurodegeneration, and crucially via pharmacological means could yield disease-modifying interventions. To investigate pharmacological IIS manipulation for therapeutic gain in neurodegeneration, I firstly characterised changes in IIS in human Alzheimer’s Disease patient brain samples, and in brain samples of mice modelling rising amyloid beta and plaque levels, or rising hyperphosphorylated tau and tangle levels; finding increased IIS at early ages in these models. I subsequently designed a bilaminar neuron and astrocyte co-culture model of acute neurodegeneration, whereby I identified that increased astrocyte Igf1 expression following a noxious stimulus is dependent on the presence of neurons during stress. I then manipulated IIS during the noxious stimulus by either knocking down increased Igf1 expression, inhibiting p-ERK with the drug Trametinib, or both. I identified that increased astrocyte Igf1 expression contributes to neuronal cell death, and that Trametinib was protective against neuronal cell death, but the mechanism of Igf1 induced neuronal cell death was not due to increase p-ERK. This confirms IIS as a viable pharmacological target for intervening in neurodegeneration.

Type: Thesis (Doctoral)
Title: Investigating the potential of therapeutically targeting the Insulin and Insulin-like Signalling Cascade in neurodegeneration
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Igf1, Neurodegeneration, Ageing, Alzheimer's disease, Insulin and Insulin-like signalling
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1553216
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