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Modulation of Neuronal Insulin Signaling Rescues Axonal Transport Defects in an Alzheimer’s Disease Model

Resource type
Thesis type
(Thesis) M.Sc.
Date created
Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Oligomeric amyloid-β peptides (AβOs), the neurotoxin implicated in AD, induce a variety of cellular insults, including dysregulation of intracellular signaling cascades and disruption of fast axonal transport. I show that modulation of insulin signaling prevents AβO-induced defects of brain-derived neurotrophic factor (BDNF) transport in wild type (tau+/+) and tau knockout (tau-/-) primary hippocampal mouse neurons. Tideglusib, an inhibitor of glycogen synthase kinase-3β (GSK3β), an insulin signaling intermediate implicated in AD, rescues BDNF transport in tau+/+ and tau-/- neurons. Furthermore, Exendin-4, an anti-diabetes agent, activates the insulin signaling pathway through glucagon like peptide-1 receptor stimulation to also rescue BDNF transport defects similarly to Tideglusib. These results indicate a protective link between insulin signaling and tau-independent transport regulation. By establishing links between insulin signaling and AβO action, my results allow for establishing novel directions for AD therapeutics.
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Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Silverman, Michael
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etd7896_OTakach.pdf 62.04 MB

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