Role of Peripheral Lipogenesis and Lipolysis in Alzheimer's Disease Pathology Disruption of brain lipid homeostasis has been demonstrated in Alzheimer's Disease (AD) and the role of lipid metabolism in the central nervous system (CNS) has been investigated extensively in this context. Indeed, many genes implicated as risk factors for both late-onset AD and early-onset AD have lipid-metabolic functions. However, little is known about how lipid metabolism in organs outside the nervous system influences the onset and progression of AD. Many systemic events precede the CNS abnormalities seen in AD suggesting that the metabolic status of non-neuronal tissues may have significant roles in pathogenesis. Epidemiology data have strongly implicated obesity, diabetes and metabolic syndrome as high-risk factors for AD. Importantly, recent genome-wide association studies (GWAS) have identified several allelic variants of PPAR?, a central regulator of lipid metabolism, that are associated with increased risk of AD, suggesting a direct role for this factor in AD. While recent studies in model organisms have revealed the importance of protein homeostasis in peripheral tissues in modulating brain AD pathology, similar mechanistic links between systemic lipid homeostasis and AD have not been made. Thus, exploring the relevance of lipogenic and lipolytic pathways in peripheral tissues to AD development is an important and largely unexplored frontier topic. Through this supplement, we propose to address the importance of lipid homeostasis in peripheral tissues in AD biology. Our overarching hypothesis is that disruption of lipid homeostasis in non- neuronal tissues contributes to AD pathogenesis. We will test this hypothesis by disrupting specific lipogenesis- and lipolysis- pathways in individual, non-neuronal tissues of the nematode model Caenorhabditis elegans strains that recapitulate A? and Tau toxicity in vivo, and examining the consequences of these lipid disruptions on the AD phenotypes of these models. These experiments are a feasible and logical extension of our current, R01-funded studies on the coordination of lipid anabolism and catabolism in metazoans. We will capitalize on the genetic tools, reagents and knowledge generated as part of our R01 project as well as our recent proficiency with worm AD models. These advantages, together with our expertise in C. elegans metabolism and aging, place us in a uniquely strong position to undertake this project expeditiously and successfully. This study will not only reveal if, and how, lipid-metabolic pathways in peripheral, non-neural tissues influence a disease of the CNS, it can also potentially expand the array of molecular and cellular targets for therapeutics against AD and other neurodegenerative disorders.
Alzheimer's Disease (AD) is a debilitating neurodegenerative disease whose molecular mechanisms are not well understood. Through this supplement, we propose to extend our studies on lipid metabolism and aging, (funded by the NIA through our R01 grant, R01AG051659), to address the role of fat metabolism in AD pathology. This research has tremendous relevance for human health because AD is a major age-related disease with enormous economic and societal ramifications for which no treatment exists. Upon successful completion, these studies can reveal fundamental knowledge about AD, open up potential therapeutic avenues for combating the disease and establish AD as a long-term research interest in our lab.
| Amrit, Francis R G; Ghazi, Arjumand (2017) Transcriptomic Analysis of C. elegans RNA Sequencing Data Through the Tuxedo Suite on the Galaxy Project. J Vis Exp : |
