title: Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Oliver
authors.initials: O
authors.lastname: Takach
authors.affiliation: Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Trevor B
authors.initials: TB
authors.lastname: Gill
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. Electronic address: masilver@sfu.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silverman
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics* / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D000077270:Exenatide; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000502:physiology*; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013268:Stimulation, Chemical; D014688:Venoms / Q000494:pharmacology; D016875:tau Proteins / Q000009:adverse effects*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D016875:tau Proteins; D000077270:Exenatide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; Axonal transport; Brain-derived neurotrophic factor; GSK3beta; Hippocampal neuron; Insulin signaling