Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in A beta oligomer-treated hippocampal neurons
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| Authors: | Gan, KJ; Silverman, MA |
| Year: | 2015 |
| Journal: | Molecular Biology of the Cell 26: 1058-1071 Article Link (DOI) PubMed |
| Title: | Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in A beta oligomer-treated hippocampal neurons |
| Abstract: | Disruption of fast axonal transport (FAT) and intracellular Ca2+ dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-beta oligomers (A beta Os), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca2+-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal A beta O binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca2+ elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of A beta Os despite compelling reports of presynaptic A beta Os in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca2+ influx through axonal voltage-gated Ca2+ channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca2+ release from the ER. This work establishes a novel role for Ca2+ dysregulation in BDNF transport disruption and tau-independent A beta toxicity in early AD. |
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