Cited by 41Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

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Gan, Kathlyn J., Silverman, Michael A.·2015·Molecular Biology of the Cell

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.

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  • In Alzheimer's disease, disease-related changes decrease BDNF axonal transport, reducing BDNF availability in the synaptic cleft and diminishing signaling through TrkB receptors.

    “These changes decrease BDNF axonal transport, resulting in reduced availability of BDNF within the synaptic cleft and consequently diminished signaling through TrkB receptors [137, 138].”

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Authors
Gan, K. J., & Silverman, M. A.
Affiliations
  • Department of Molecular Biology and Biochemistry and
  • University of British Columbia (CA)
Corresponding author
Silverman, Michael A.
Venue
Molecular Biology of the Cell
Published
2015-03-15
Volume
26
Issue
6
Pages
1058-1071
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
OpenAlex
W2164137922
Cited by
41
References
76
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Simon Fraser University
  • Canadian Institutes of Health Research (90396)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid-beta oligomers, fast axonal transport, intracellular calcium dysregulation, calcineurin, dendrites, axons, voltage-gated calcium channels, dantrolene, endoplasmic reticulum calcium release, hippocampal neurons
MeSH terms
Alzheimer Disease, Animals, Axons, Calcium Channel Blockers, Cells, Cultured, Dendrites, Female, Hippocampus, Male, Peptide Fragments, Calcium Channels, Amyloid beta-Peptides, Mice, Knockout, Brain-Derived Neurotrophic Factor, Calcineurin, Ryanodine Receptor Calcium Release Channel, Calcium Signaling, Protein Transport

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