Role of Relish/NFkB Apoptosis Pathway in Amyloid-beta 42 mediated neurodegeneration in Alzheimer’s disease.
Alzheimer’s disease (AD) is a neurodegenerative disease, which affects the mental functions of the patients. This disorder progresses with age and does not have a cure to-date. One of the reasons for the manifestation of AD is the accumulation of amyloid-beta- 42 (Aβ42) proteins. In our study, we have used Drosophila as our model organism (as 75% of the genetic machinery is conserved between flies and humans), and have developed a model where when human Aβ42 is misexpressed in the differentiating eye, triggers cell death in the retinal neurons. We have also identified a soy-based anti- inflammatory protein, Lunasin, which can block Aβ42 mediated cell death by downregulating the NFkB pathway (which lead to translation of apoptotic proteins of Jun-N Terminal Kinase (JNK) pathway). In order to discern the exact mechanism by which Lunasin prevents neuronal cell death (caused by the accumulation of Aβ42 proteins), we have developed transgenic flies, which can produce human Aβ42 and Aβ42+Lunasin in the Drosophila eye. Our hypothesis states that manipulating the Relish protein complex of the Imd-NFKB pathway could lead to activity variation in JNK pathway in Aβ42+Lunasin flies. To test our hypothesis, we used GAL4/UAS system genetic technique and misexpressed relish and relish RNAi in human Aβ42, Aβ42+Lunasin background, and checked for the resultant phenotypes in (1) the larval eye imaginal discs and in (2) the adult eyes. Our data showed that downregulating Relish rescues neurodegenerative phenotypes seen in Alzheimer’s flies. It suggests that the Imd-NFKB pathway plays a positive role in Lunasin’s ability to mitigate the neuronal cell death cause by the accumulation of Aβ42 plaques. These studies have significant bearing on the use of NFKB members as biomarkers or druggable targets and generate new insights into the mechanism by which Aβ42 mediated neurodegeneration cell death can be blocked in the future.
Primary Advisor's Department
Stander Symposium poster
"Role of Relish/NFkB Apoptosis Pathway in Amyloid-beta 42 mediated neurodegeneration in
Alzheimer’s disease." (2018). Stander Symposium Posters. 1233.