Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in A? oligomer-treated hippocampal neurons.

ABSTRACT: Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-? oligomers (A?Os), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal A?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 Ca(2+) 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?Os despite compelling reports of presynaptic A?Os in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca(2+) influx through axonal voltage-gated Ca(2+) channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca(2+) release from the ER. This work establishes a novel role for Ca(2+) dysregulation in BDNF transport disruption and tau-independent A? toxicity in early AD.

SUBMITTER: Gan KJ 

PROVIDER: S-EPMC4357506 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature