title: Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ 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-β oligomers (AβOs), 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 AβO 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 AβOs despite compelling reports of presynaptic AβOs 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 Aβ toxicity in early AD.
authors.affiliation: Department of Molecular Biology and Biochemistry and.
authors.forename: Kathlyn J
authors.initials: KJ
authors.lastname: Gan
authors.affiliation: Department of Molecular Biology and Biochemistry and Department of Biological Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada Brain Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada masilver@sfu.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silverman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000502:physiology*; D021381:Protein Transport; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010446:Peptide Fragments; D019837:Ryanodine Receptor Calcium Release Channel; C075222:amyloid beta-protein (1-42); D019703:Calcineurin