PMID- 23783030
OWN - NLM
STAT- MEDLINE
DCOM- 20140331
LR  - 20211021
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 24
IP  - 16
DP  - 2013 Aug
TI  - Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport 
      via calcineurin activation in cultured hippocampal neurons.
PG  - 2494-505
LID - 10.1091/mbc.E12-12-0858 [doi]
AB  - Disruption of fast axonal transport (FAT) is an early pathological event in 
      Alzheimer's disease (AD). Soluble amyloid-beta oligomers (AbetaOs), increasingly 
      recognized as proximal neurotoxins in AD, impair organelle transport in cultured 
      neurons and transgenic mouse models. AbetaOs also stimulate hyperphosphorylation of 
      the axonal microtubule-associated protein, tau. However, the role of tau in FAT 
      disruption is controversial. Here we show that AbetaOs reduce vesicular transport of 
      brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both 
      wild-type and tau-knockout mice, indicating that tau is not required for 
      transport disruption. FAT inhibition is not accompanied by microtubule 
      destabilization or neuronal death. Significantly, inhibition of calcineurin 
      (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues 
      BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen 
      synthase kinase 3beta, downstream targets of CaN, prevents BDNF transport defects 
      induced by AbetaOs. We further show that AbetaOs induce CaN activation through 
      nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and 
      demonstrate that tau is not required for AbetaO-induced BDNF transport disruption.
FAU - Ramser, Elisa M
AU  - Ramser EM
AD  - Department of Biological Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, 
      Canada.
FAU - Gan, Kathlyn J
AU  - Gan KJ
FAU - Decker, Helena
AU  - Decker H
FAU - Fan, Emily Y
AU  - Fan EY
FAU - Suzuki, Matthew M
AU  - Suzuki MM
FAU - Ferreira, Sergio T
AU  - Ferreira ST
FAU - Silverman, Michael A
AU  - Silverman MA
LA  - eng
GR  - 90396/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130619
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Mapt protein, mouse)
RN  - 0 (Tubulin)
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.1.3.16 (Calcineurin)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Axonal Transport/*physiology
MH  - Biological Transport
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Calcineurin/drug effects/*metabolism
MH  - Calcineurin Inhibitors
MH  - Calcium Signaling
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors
MH  - Glycogen Synthase Kinase 3 beta
MH  - Hippocampus/metabolism
MH  - Immunosuppressive Agents/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - Microtubules/metabolism
MH  - Neurons/metabolism
MH  - Phosphorylation
MH  - Protein Phosphatase 1/antagonists & inhibitors/drug effects
MH  - Protein Processing, Post-Translational
MH  - Tacrolimus/pharmacology
MH  - Tubulin/metabolism
MH  - tau Proteins/*metabolism
PMC - PMC3744947
EDAT- 2013/06/21 06:00
MHDA- 2014/04/01 06:00
PMCR- 2013/10/30
CRDT- 2013/06/21 06:00
PHST- 2013/06/21 06:00 [entrez]
PHST- 2013/06/21 06:00 [pubmed]
PHST- 2014/04/01 06:00 [medline]
PHST- 2013/10/30 00:00 [pmc-release]
AID - mbc.E12-12-0858 [pii]
AID - E12-12-0858 [pii]
AID - 10.1091/mbc.E12-12-0858 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2013 Aug;24(16):2494-505. doi: 10.1091/mbc.E12-12-0858. Epub 2013 
      Jun 19.