Dysregulation of neuronal calcium signaling impairs axonal transport independent of tau in a model of Alzheimer's disease

Resource type
Thesis type
(Thesis) Ph.D.
Date created
2014-10-30
Authors/Contributors
Abstract
Neurons rely on microtubule-based, fast axonal transport of proteins and organelles for development, communication and survival. FAT impairment precedes overt cellular toxicity in multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Intracellular Ca2+ dysregulation is also widely implicated in early AD pathogenesis; however, its role in transport impairment is unknown. Our lab was first to demonstrate that soluble amyloid-β oligomers (AβOs), proximal neurotoxins in AD, impair vesicular transport of axonal brain-derived neurotrophic factor (BDNF). Contrary to a central paradigm, I show that BDNF transport is blocked independent of the microtubule-associated protein, tau, microtubule destabilization, and acute cell death. Significantly, BDNF transport is impaired by non-excitotoxic activation of calcineurin (CaN), a Ca2+-dependent phosphatase. Based on these findings, I investigated Ca2+-dependent mechanisms that underlie the spatiotemporal progression of AβO-induced transport defects and dysregulate KIF1A, the primary kinesin motor required for BDNF transport. Because CaN and its effectors, protein phosphatase-1 (PP1) and glycogen synthase kinase 3β (GSK3β), are present in both dendrites and axons, I investigated if postsynaptic AβO binding impairs dendritic transport prior to FAT disruption. AβOs induce dendritic and axonal BDNF transport defects simultaneously; however, maximal dendritic transport defects are observed prior to maximal impairment of FAT. I correlated the spatiotemporal progression of transport defects with Ca2+ elevation and CaN activation in dendrites and subsequently in axons. Postsynaptic CaN activation converges on axonal Ca2+ dysregulation to impair FAT. Specifically, AβOs colocalize with axonal VGCCs, and blocking VGCCs prevents FAT defects. Finally, BDNF transport defects are prevented by dantrolene, a compound that reduces Ca2+-induced- Ca2+ release through ryanodine receptors in axonal and dendritic ER membranes. Together, these mechanisms activate CaN-PP1-GSK3β signaling and lead to inhibitory phosphorylation of KIF1A at a highly conserved consensus site within its dimerization domain. Collectively, this thesis establishes novel roles for Ca2+ dysregulation in BDNF transport disruption and tau-independent toxicity during early AD pathogenesis.
Document
Identifier
etd8700
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Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Silverman, Michael
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