Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons

• Published in: Molecular biology of the cell Vol. 24; no. 16; pp. 2494 - 2505
• Main Authors: Ramser, Elisa M, Gan, Kathlyn J, Decker, Helena, Fan, Emily Y, Suzuki, Matthew M, Ferreira, Sergio T, Silverman, Michael A
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 15-08-2013
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Animals; Axonal Transport - physiology; Biological Transport; Brain-Derived Neurotrophic Factor - metabolism; Calcineurin - drug effects; Calcineurin - metabolism; Calcineurin Inhibitors; Calcium Signaling; Cells, Cultured; Enzyme Activation; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; Hippocampus - metabolism; Immunosuppressive Agents - pharmacology; Mice; Mice, Knockout; Microtubules - metabolism; Neurons - metabolism; Phosphorylation; Protein Phosphatase 1 - antagonists & inhibitors; Protein Phosphatase 1 - drug effects; Protein Processing, Post-Translational; Tacrolimus - pharmacology; tau Proteins - metabolism; Tubulin - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E12-12-0858

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs 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 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.