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Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons.
Neurobiol Aging 2015; 36(3):1378-82NA

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+Show Affiliations

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25543463

Citation

Takach, Oliver, et al. "Modulation of Insulin Signaling Rescues BDNF Transport Defects Independent of Tau in Amyloid-β Oligomer-treated Hippocampal Neurons." Neurobiology of Aging, vol. 36, no. 3, 2015, pp. 1378-82.
Takach O, Gill TB, Silverman MA. Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons. Neurobiol Aging. 2015;36(3):1378-82.
Takach, O., Gill, T. B., & Silverman, M. A. (2015). Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons. Neurobiology of Aging, 36(3), pp. 1378-82. doi:10.1016/j.neurobiolaging.2014.11.018.
Takach O, Gill TB, Silverman MA. Modulation of Insulin Signaling Rescues BDNF Transport Defects Independent of Tau in Amyloid-β Oligomer-treated Hippocampal Neurons. Neurobiol Aging. 2015;36(3):1378-82. PubMed PMID: 25543463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons. AU - Takach,Oliver, AU - Gill,Trevor B, AU - Silverman,Michael A, Y1 - 2014/12/03/ PY - 2014/06/26/received PY - 2014/10/21/revised PY - 2014/11/25/accepted PY - 2014/12/30/entrez PY - 2014/12/30/pubmed PY - 2015/11/13/medline KW - Alzheimer's disease KW - Axonal transport KW - Brain-derived neurotrophic factor KW - GSK3beta KW - Hippocampal neuron KW - Insulin signaling SP - 1378 EP - 82 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 36 IS - 3 N2 - 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. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/25543463/Modulation_of_insulin_signaling_rescues_BDNF_transport_defects_independent_of_tau_in_amyloid_β_oligomer_treated_hippocampal_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-4580(14)00789-1 DB - PRIME DP - Unbound Medicine ER -