AD and related diseases are the most crippling cognitive threat to our aging population. There is no cure for AD, and this is partly due to poor understanding of how aging and inflammation impacts tau pathogenesis. By 2050, it is expected that the United States will spend $1.2 trillion to maintain the constantly deteriorating quality of life of 16 million Americans with AD (Thies et al., 2013). As a result, there is an urgent need to identify effective therapeutic interventions with clear molecular mechanisms that ameliorate risk for AD in order to find therapeutic targets. Age is the primary risk factor for neurodegenerative diseases. One factor thought to contributes to a loss of resilience to pathological insults, such as tau, with age is a background of inflammation (Heneka et al., 2015). Unfortunately, the underlying molecular alterations that lead to inflammation with age and therapeutic approaches to improve resiliency are not fully understood (Bennet et al., 1996; Niccoli and Partridge, 2012; Michaud et al., 2013; Moll et al., 2014). One of the major contributors to this aging ?environment? is an activation of the innate immune system. We show that age is a critical factor contributing to tau pathology Further, we propose exosomes from human adipose derived stem cells (hASC?s) as a novel intervention to modulate inflammation that will be a useful therapeutic for AD and related tauopathies. The secretome of stem cells, including exosomes are powerful modulators of inflammation: Human adipose-derived stem cells (hASC?s) manifest a secretome containing exosomes that is capable of modulating immune function as part of their mechanism of action (Kim et al., 2016; Long et al., 2017). Of the cargo secreted in hASC exosomes, lncRNA MALAT1 controls key biological processes including modulating immune cell expression of TNFa and IL-6 following LPS stimulation (Zhao et al., 2016). The overall objective is to establish the therapeutic impact of hASC exosomes on tau pathogenesis in the background of aging. We will evaluate this in models of tauopathies, using age as a primary variable. We will express tau at different ages and evaluate functional outcomes, pathology, microglial phenotype. hASC exosome treatment will be induced with the hypothesis that this will reduce tau pathology. We will explore the molecular targets of hASC exosomes with age in microglia using proteomic profiling and ex vivo study of microglial function. We will further address the effect of age and hASC exosomes on tau pathology and tau spreading. Our data show that hASC exosomes reduce tau phosphorylation in Tg4510 mice. Thus, there is an intersection of direct and indirect actions on tau pathogenesis that is influenced by age.

Public Health Relevance

Alzheimer?s disease (AD) and related diseases of aging are the most crippling cognitive threat to our aging population and there is no cure for AD, and this is partly due to poor understanding of how aging and inflammation impacts tau pathogenesis. In this proposal we consider age and inflammation as a primary variable that contributes to pathology associated with AD models. We have identified exosomes from stem cells as a novel target to reduce innate immune function in the aged brain, the impact of these studies, if successful would be to identify novel approaches to therapeutics of aging and neurodegenerative disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Yang, Austin Jyan-Yu
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University of South Florida
Schools of Medicine
United States
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