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Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic Caenorhabditis elegans
Author(s) -
Benbow Sarah J,
Strovas Timothy J,
Darvas Martin,
Saxton Aleen,
Kraemer Brian C
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047426
Subject(s) - transgene , caenorhabditis elegans , neurodegeneration , genetically modified mouse , biology , tauopathy , tau protein , neuroscience , disease , microbiology and biotechnology , amyloid (mycology) , alzheimer's disease , phenotype , medicine , genetics , gene , pathology , botany
Background Aggregates of Aβ peptide and the microtubule‐associated protein tau are key molecular hallmarks of Alzheimer's disease (AD). However, the interaction between these two pathologies and the mechanisms underlying disease progression have remained unclear. Numerous failed clinical trials suggest the necessity for greater mechanistic understanding in order to refine strategies for therapeutic discovery and development. Method To this end, we have generated a transgenic Caenorhabditis elegans model expressing both human Aβ 1‐42 peptide and human tau protein pan‐neuronally. We used behavioral, morphological and biochemical assays to assess pathological progression. Results We observed exacerbated behavioral dysfunction and age‐dependent neurodegenerative changes in the Aβ;tau transgenic animals. Further, these changes occurred in the Aβ;tau transgenic animals at greater levels than worms harboring either the Aβ 1‐42 or tau transgene alone and interestingly without changes to the levels of tau expression, phosphorylation or aggregation. Functional changes were partially rescued with the introduction of a genetic suppressor of tau pathology. Conclusion Taken together, the data herein support a synergistic role for both Aβ and tau in driving neuronal dysfunction seen in AD. Additionally, we believe that the utilization of the genetically tractable C. elegans model will provide a key resource for dissecting mechanisms driving AD molecular pathology.