Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-beta oligomer-treated hippocampal neurons
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| Authors: | Takach, O; Gill, TB; Silverman, MA |
| Year: | 2015 |
| Journal: | Neurobiology of Aging 36: 1378-1382 Article Link (DOI) PubMed |
| Title: | Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-beta oligomer-treated hippocampal neurons |
| Abstract: | Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (A beta Os), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3 beta. By this mechanism, A beta Os may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in A beta O-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3 beta rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in A beta O-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression. (C) 2015 Elsevier Inc. All rights reserved. |
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