Dysregulation of neuronal calcium signaling impairs axonal transport independent of tau in a model of Alzheimer's disease
Year: 2014
Type: dissertation
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 Ca 2+ 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 microtubuleassociated protein, tau, microtubule destabilization, and acute cell death.Significantly, BDNF transport is impaired by non-excitotoxic activation of calcineurin (CaN), a Ca 2+dependent phosphatase.Based on these findings, I investigated Ca 2+ -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 Ca 2+ elevation and CaN activation in dendrites and subsequently in axons.Postsynaptic CaN activation converges on axonal Ca 2+ 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 Ca 2+ -induced-Ca 2+ 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 Ca 2+ dysregulation in BDNF transport disruption and tau-independent toxicity during early AD pathogenesis.
Source: Summit (Simon Fraser University)
Author: Kathlyn J. Gan
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Simon Fraser University, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada
OpenAlex ID: W2291837103