Two clone system to determine complex signaling between wild-type and Aβ42 expressing neurons in Alzheimer’s Disease.

Alzheimer’s Disease (hereafter AD) is an irreversible neurodegenerative disease causing death of millions of elderly people every year. One of the reasons for AD is abnormal cleavage of the Amyloid precursor protein (APP), which forms a 42 amino acid long hydrophobic polypeptide (hereafter Aβ42) which form aggregates leading to amyloid plaques. This Aβ42 forms plaque that leads to neuronal cell death. We are trying to understand the genetic underpinnings behind the onset of this deadly disease using Drosophila melanogaster eye as our model system. We have generated and optimized a two-clone system in our lab to understand the crosstalk between the plaque forming neurons and the adjacent wild type neurons. The onset of AD initiates with a few neurons which start producing amyloid plaques, which then triggers cell death. One of the questions is: Which neuronal population is affected? Our system utilizes the FLP/FRT mediated recombination to produce two types of neuronal cell population where strong GFP reporter marks the Aβ42 misexpressing neurons, and the neighboring wild-type neurons are marked by the absence of GFP. Our preliminary data suggests that the Aβ42 misexpressing neurons survive at the expense of the neighboring wild type cells. Thus, we believe that there are certain signals, which emanates from these Aβ42 plaque producing neurons towards the wild type neurons, which causes them to die. We have identified evolutionarily conserved Jun-N-Terminal Kinase (JNK) Signaling pathway as one of the genetic modifiers of Aβ42 mediated neurodegeneration, which induces neuronal death. With the help of our two-clone system, we want to understand which neuronal cells (Aβ42 misexpressed vs wild type cells) and how, the JNK signaling triggers cell death. We will test reporters and antibodies against the members of JNK signaling pathway to address our hypothesis. Furthermore, identifying the genetic biomarkers of the Alzheimer’s disease with the help of our genetic tool can be utilized in finding therapeutic targets in the future.https://ecommons.udayton.edu/stander_posters/2281/thumbnail.jp