| First Author | Takach O | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 3 | Pages | 1378-82 |
| PubMed ID | 25543463 | Mgi Jnum | J:221692 |
| Mgi Id | MGI:5641318 | Doi | 10.1016/j.neurobiolaging.2014.11.018 |
| Citation | Takach O, et al. (2015) Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-beta oligomer-treated hippocampal neurons. Neurobiol Aging 36(3):1378-82 |
| abstractText | Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AbetaOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3beta. By this mechanism, AbetaOs 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 AbetaO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3beta 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 AbetaO-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. |
