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The amyloid-[beta] 42 (A[beta]42) peptide has been suggested to promote tau phosphorylation and toxicity in Alzheimer's disease (AD) pathogenesis; however, the underlying mechanisms are not fully understood. Using transgenic Drosophila expressing both human A[beta]42 and tau, we show here that tau phosphorylation at Ser262 plays a critical role in A[beta]42-induced tau toxicity. Co-expression of A[beta]42 increased tau phosphorylation at AD-related sites including Ser262, and enhanced tau-induced neurodegeneration. In contrast, formation of either sarkosyl-insoluble tau or paired helical filaments was not induced by A[beta]42. Co-expression of A[beta]42 and tau carrying the non-phosphorylatable Ser262Ala mutation did not cause neurodegeneration, suggesting that the Ser262 phosphorylation site is required for the pathogenic interaction between A[beta]42 and tau. We have recently reported that the DNA damage-activated Checkpoint kinase 2 (Chk2) phosphorylates tau at Ser262 and enhances tau toxicity in a transgenic Drosophila model. We detected that expression of Chk2, as well as a number of genes involved in DNA repair pathways, was increased in the A[beta]42 fly brains. The induction of a DNA repair response is protective against A[beta]42 toxicity, since blocking the function of the tumor suppressor p53, a key transcription factor for the induction of DNA repair genes, in neurons exacerbated A[beta]42-induced neuronal dysfunction. Our results demonstrate that tau phosphorylation at Ser262 is crucial for A[beta]42-induced tau toxicity in vivo, and suggest a new model of AD progression in which activation of DNA repair pathways is protective against A[beta]42 toxicity but may trigger tau phosphorylation and toxicity in AD pathogenesis.

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