Article
In vivo induction of membrane damage by β-amyloid peptide oligomers. Public Deposited
https://scholar.colorado.edu/concern/articles/rb68xc402
- Abstract
- Exposure to the β-amyloid peptide (Aβ) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Aβ oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Aβ oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Aβ exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Aβ induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Aβ Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer's disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Aβ multimerization and thus the formation of potentially pore-forming oligomers. We propose that Aβ-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.
- Creator
- Date Issued
- 2018-11-29
- Academic Affiliation
- Journal Title
- Journal Issue/Number
- 1
- Journal Volume
- 6
- File Extent
- 131-131
- Subject
- Morpholinos
- Sphingomyelin Phosphodiesterase
- Amyloid beta-Peptides
- Acrylates
- Phosphorylation
- Genetically Modified
- Rats
- Models
- Cultured
- Caenorhabditis elegans
- Hemolysin Proteins
- Neurons
- Mammalian
- Peptide Fragments
- Intestines
- Embryo
- Endosomes
- Animals
- Hippocampus
- Humans
- Wound Healing
- Animal
- Endotoxins
- Vesicular Transport Proteins
- Bacterial Proteins
- Cells
- Caenorhabditis elegans Proteins
- Enzyme Inhibitors
- Last Modified
- 2019-12-05
- Identifier
- PubMed ID: 30497524
- Resource Type
- Rights Statement
- DOI
- ISSN
- 2051-5960
- Language
- License
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inVivoInductionOfMembraneDamageByAmyloidPeptideOligome.pdf | 2019-12-05 | Public | Download |