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F1‐01‐05: Studying mechanisms underlying Aß42‐induced tau toxicity in transgenic Drosophila models
Author(s) -
Iijima Koichi
Publication year - 2010
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 - 10.1016/j.jalz.2010.05.174
Subject(s) - phosphorylation , neurodegeneration , transgene , toxicity , dephosphorylation , genetically modified mouse , biology , microbiology and biotechnology , dna damage , tau protein , biochemistry , alzheimer's disease , chemistry , dna , phosphatase , gene , pathology , medicine , disease , organic chemistry
Background: Accumulation of amyloid-ß 42 (Aß42) peptide and hyperphosphorylated ntau protein in brains are pathological hallmarks in Alzheimer’s disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at AD-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau. Aß peptides have been shown to induce tau phosphorylation and toxicity in cellular and animal models, however, its underlying mechanisms are not fully understood. Methods: We have used transgenic Drosophila expressing both human Aß42 and tau proteins to investigate the molecular mechanisms underlying toxic interaction between Aß42 and tau. Results: We found that co-expression of human Aß42 and tau increased tau phosphorylation at the AD-related sites and enhanced tau-induced neurodegeneration in transgenic flies. Introduction of a non-phosphorylatable alanine mutation at one of these sites significantly reduced Aß42-induced enhancement of tau toxicity, suggesting that this phosphorylation site is involved in the pathogenic interaction between tau and Aß42. We also demonstrate that activation of DNA repair response is involved in enhancement of tau toxicity by Aß42 in Drosophila. Conclusions: Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that activation of the DNA repair response is one of the mechanisms that mediate Aß42-induced abnormal phosphorylation and toxicity of tau in vivo.