| First Author | Ramser EM | Year | 2013 |
| Journal | Mol Biol Cell | Volume | 24 |
| Issue | 16 | Pages | 2494-505 |
| PubMed ID | 23783030 | Mgi Jnum | J:310683 |
| Mgi Id | MGI:6763729 | Doi | 10.1091/mbc.E12-12-0858 |
| Citation | Ramser EM, et al. (2013) Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons. Mol Biol Cell 24(16):2494-505 |
| abstractText | 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. |
