Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons
| Autor: | Trevor B. Gill, Oliver Takach, Michael A. Silverman |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Aging
medicine.medical_specialty tau Proteins Axonal Transport Hippocampus Glycogen Synthase Kinase 3 Downregulation and upregulation Neurotrophic factors Alzheimer Disease Internal medicine medicine Neurotoxin Animals Hypoglycemic Agents Insulin Glycogen synthase Protein kinase B Cells Cultured Brain-derived neurotrophic factor Mice Knockout Neurons Amyloid beta-Peptides Glycogen Synthase Kinase 3 beta biology Venoms General Neuroscience Brain-Derived Neurotrophic Factor Stimulation Chemical Insulin receptor Endocrinology nervous system Axoplasmic transport biology.protein Exenatide Neurology (clinical) Geriatrics and Gerontology Peptides Proto-Oncogene Proteins c-akt Developmental Biology Signal Transduction |
| Zdroj: | Neurobiology of aging. 36(3) |
| ISSN: | 1558-1497 |
| Popis: | Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AβOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3β. By this mechanism, AβOs 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 AβO-treated primary neurons from wild type (tau +/+ ) and tau knockout (tau −/− ) mice. Remarkably, inhibition of glycogen synthase kinase-3β 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 AβO-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. |
| Databáze: | OpenAIRE |
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