Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons

Neurobiol Aging. 2015 Mar;36(3):1378-82. doi: 10.1016/j.neurobiolaging.2014.11.018. Epub 2014 Dec 3.


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.

Keywords: Alzheimer's disease; Axonal transport; Brain-derived neurotrophic factor; GSK3beta; Hippocampal neuron; Insulin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / prevention & control*
  • Amyloid beta-Peptides / adverse effects*
  • Animals
  • Axonal Transport / genetics*
  • Axonal Transport / physiology*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cells, Cultured
  • Exenatide
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / cytology*
  • Hypoglycemic Agents / pharmacology
  • Insulin / physiology*
  • Mice, Knockout
  • Neurons / metabolism*
  • Peptides / pharmacology
  • Proto-Oncogene Proteins c-akt / physiology*
  • Signal Transduction / physiology*
  • Stimulation, Chemical
  • Venoms / pharmacology
  • tau Proteins / adverse effects*


  • Amyloid beta-Peptides
  • Brain-Derived Neurotrophic Factor
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Venoms
  • tau Proteins
  • Exenatide
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3