Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 24, Issue 16, Pages 2494-2505Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-12-0858
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Funding
- National Science and Engineering Research Council of Canada [327100-06]
- Canadian Foundation for Innovation [12793]
- Canadian Institutes of Health Research [90396]
- C.D. Nelson Memorial Graduate Scholarship from Simon Fraser University
- National Science and Engineering Research Council of Canada
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- National Institute of Translational Neuroscience
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (Brazil)
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Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-beta oligomers (A beta Os), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. A beta Os also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that A beta Os 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 3 beta, downstream targets of CaN, prevents BDNF transport defects induced by A beta Os. We further show that A beta Os induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for A beta O-induced BDNF transport disruption.
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