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

作者：Ramser Elisa M; Gan Kathlyn J; Decker Helena; Fan Emily Y; Suzuki Matthew M; Ferreira Sergio T; Silverman Michael A^*

来源：Molecular Biology of the Cell, 2013, 24(16): 2494-2505.

DOI：10.1091/mbc.E12-12-0858

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer%26apos;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.

• 出版日期2013-8-15
• 单位河北医科大学