The formation of A2 oligomers (ADDLs) and their subsequent binding and toxicity to neurons are seen as the initial events in Alzheimer
The first aim of this proposal investi- gates the protective mechanism by which insulin prevents ADDL binding with the hypothesis that insulin treat- ment causes the removal of surface proteins to which ADDLs attach. Intracellular uptake and extracellular re- lease of proteins will be distinguished using reversible surface biotinylation with co-immunoprecipitation. Using pharmacological inhibitors, I will determine which insulin signaling cascades are responsible for the anti-ADDL effects of insulin. These cascades will be validated for their activation kinetics using phospho-specific antibod- ies coupled with fluorescence microscopy, My second aim evaluates the ability of naturally-derived insulin mi- metics to act as anti-ADDL therapeutics and evaluate their mode of action in neural cells. As a result of this project, we will better understand insulin signaling in the CNS. More importantly, we will likely have identified new lead compounds for AD therapeutics.
The goal of this project is to understand how brain cells respond to insulin. The response to insulin is important for normal cell functioning, and it seems to be disrupted in Alzheimer
| Pitt, Jason; Wilcox, Kyle C; Tortelli, Vanessa et al. (2017) Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound A? oligomers. Mol Biol Cell 28:2623-2636 |
| Pitt, Jason; Wilcox, Kyle C; Tortelli, Vanessa et al. (2017) Neuroprotective astrocyte-derived insulin/IGF-1 stimulate endocytic processing and extracellular release of neuron-bound A? oligomers. Mol Biol Cell : |
| Pitt, Jason; Thorner, Michael; Brautigan, David et al. (2013) Protection against the synaptic targeting and toxicity of Alzheimer's-associated A? oligomers by insulin mimetic chiro-inositols. FASEB J 27:199-207 |
