Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons
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| Authors: | Ramser, EM; Gan, KJ; Decker, H; Fan, EY; Suzuki, MM; Ferreira, ST; Silverman, MA |
| Year: | 2013 |
| Journal: | Mol. Biol. Cell 24: 2494-2505 Article Link (DOI) PubMed |
| Title: | Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons |
| Abstract: | 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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