Dissecting the modulatory functions of interleukin-17 in Alzheimer's Disease

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ABSTRACT Alzheimer’s Disease (AD) is one of the most common causes of dementia, affecting over 5 million elderly patients in 2020. The affected patient number will likely grow in the United States and reach 10 million by 2040, representing a significant challenge to public health care. It is thus imperative to find novel ways that offer mechanistic insights into the onset and the progression of AD. While a growing body of evidence indicates the critical function of innate immune systems in AD, relatively few studies investigated mechanisms by which adaptive immune cells contribute to the pathogenesis of AD. Along with genetic factors, environmental factors are critical contributors to driving neurodegenerative disorders, including AD. Gut microbes, which have been extensively studied for their roles in shaping the host’s immune function, are being recognized as one of these non-genetic factors that define a threshold to either maintaining homeostasis or developing diseases. Intriguingly, AD patients often display gut dysbiosis, suggesting that the make-up of gut-residing bacteria may affect the development and progression of AD. While many studies in recent years have shown that gut-residing bacteria and immune cells affect brain function, the underlying mechanisms by which gut bacteria empower peripheral immune cells to influence AD-related phenotypes are unknown. Among the many immune cell types, Th17 cells are uniquely positioned to relay signals from gut-residing bacteria to the brain. These cells are induced in the gut mucosa in response to a commensal bacterium and can migrate into the meninges. We and others have also shown that a receptor for IL-17a, namely IL-17Ra, is expressed in the adult brain and facilitates the communication between the immune and nervous systems. In the proposed application, we will assess the contributing roles of the triad of gut bacteria-peripheral Th17 cells-brain IL-17Ra in promoting AD-related pathologies and cognitive decline. We will first identify the role of IL-17a-producing cells in promoting AD-related pathogenesis and determine the contributing roles of gut- residing bacteria that enhance Th17 cell biogenesis in the development of AD. Second, we will uncover the underlying mechanisms by which IL-17a affects brain cells during AD development. Successful completion of this study will likely lead to future human studies identifying preventive and therapeutic measures, such as probiotics or blocking antibodies, to suppress the IL-17a responses in patients with a high risk of developing AD-related cognitive decline.