Modulation of Neuronal Insulin Signaling Rescues Axonal Transport Defects in an Alzheimer's Disease Model
Author | : Oliver Peter Takach |
Publisher | : |
Total Pages | : 0 |
Release | : 2013 |
Genre | : Alzheimer's disease |
ISBN | : |
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Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Oligomeric amyloid-[beta] peptides (A[beta]Os), 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 A[beta]O-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-3[beta] (GSK3[beta]), 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 A[beta]O action, my results allow for establishing novel directions for AD therapeutics.