Background: Alzheimer's disease (AD) is an age related progressive neurodegenerative disorder. One of the reasons for Alzheimer's neuropathology is the generation of large aggregates of Aß42 that are toxic in nature and induce oxidative stress, aberrant signaling and many other cellular alterations that trigger neuronal cell death. However, the exact mechanisms leading to cell death are not clearly understood.
Methodology/Principal Findings: We employed a Drosophila eye model of AD to study how Aß42 causes cell death. Misexpression of higher levels of Aß42 in the differentiating photoreceptors of fly retina rapidly induced aberrant cellular phenotypes and cell death. We found that blocking caspase-dependent cell death initially blocked cell death but did not lead to a significant rescue in the adult eye. However, blocking the levels of c-Jun NH (2)-terminal kinase (JNK) signaling pathway significantly rescued the neurodegeneration phenotype of Aß42 misexpression both in eye imaginal disc as well as the adult eye. Misexpression of Aß42 induced transcriptional upregulation of puckered (puc), a downstream target and functional read out of JNK signaling. Moreover, a three-fold increase in phospho-Jun (activated Jun) protein levels was seen in Aß42 retina as compared to the wild-type retina. When we blocked both caspases and JNK signaling simultaneously in the fly retina, the rescue of the neurodegenerative phenotype is comparable to that caused by blocking JNK signaling pathway alone.
Conclusions/Significance: Our data suggests that accumulation of Aß42 plaques induces JNK signaling in neurons and induction of JNK contributes to Aß42 mediated cell death. Therefore, inappropriate JNK activation may indeed be relevant to the AD neuropathology, thus making JNK a key target for AD therapies.
Copyright © 2011, Tare et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credite
Tare, Meghana; Modi, Rohan; Nainaparampil, Jaison; Puli, Oorvashi Roy; Bedi, Shimpi; Fernandez-Funez, Pedro; Kango-Singh, Madhuri; and Singh, Amit, "Activation of JNK Signaling Mediates Amyloid-ß- Dependent Cell Death" (2011). Biology Faculty Publications. 127.
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Acknowledgments: PF-F is supported by the NIH grant DP2 OD002721-01. MKS is supported by the Knight's Templar Eye Foundation. This work is supported by a NIH grant (1R15 HD064557-01), start-up support from the University of Dayton, and the Ohio Cancer Research Associates seed grant awarded to AS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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