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Alzheimer’s disease (AD), a common form of dementia and an age related progressive neurodegenerative disorder affects 21 million people globally. AD manifests as memory loss and reduced cognitive ability. One of the hallmarks of AD is formation of the Amyloid-beta (Aβ42) plaques, which initiates oxidative stress due to impaired signaling and finally leads to the death of neurons by unknown mechanism. It is known that loss of neurons in AD is not an outcome of a single gene mutation rather it is an impairment of several signaling pathways involved in growth and survival. The short life cycle of 12-15 days, a plethora of genetic tools, and about 70% similar genetic makeup to that of the humans, makes Drosophila an ideal model to study human disease. We have developed a highly versatile Drosophila melanogaster model to understand the role of these highly conserved signaling pathways in AD. We misexpressed high levels of human Aβ42 protein in the developing fly retina which mimics AD like neuropathology. Our aim is to use this model to discern the role of signaling pathways involved in neurodegeneration. We performed a forward genetic screen and identified members of highly conserved Wingless (Wg) pathway as modifiers of the Aβ42 mediated neurodegeneration. We have demonstrated that blocking Wg signaling pathway, can suppress the Aβ42 mediated neurodegeneration. My future goal is to investigate if we can use chemical inhibitors to block Wg signaling in neurons expressing high levels of Aβ42 and thereby prevent neurodegeneration in the Drosophila eye. We will test antagonists and agonists of Wg signaling to determine if they can work as chemical inhibitor of Aβ42 mediated neurodegeneration. I will be testing in these studies whether Wg can be a good therapeutic target in our in vivo animal system.
Madhuri Kango-Singh, Amit Singh
Primary Advisor's Department
Stander Symposium poster
"Role of Wingless (Wg) signaling pathway in Aβ42 mediated neurodegeneration in Alzheimer’s disease" (2016). Stander Symposium Projects. 775.