The ultimate goal of this study is to advance our understanding of the complexity of Alzheimer’s disease (AD) pathophysiology and to provide invaluable preclinical information on new treatment strategies. Sporadic AD involves multiple genetic risk factors. One of the top genetic risk factors for AD is SORL1; association between genetic variants of SORL1 and late-onset AD has been repeatedly revealed in genome-wide association studies. Furthermore, nonsense and missense mutations of SORL1 cause autosomal dominant early-onset AD, supporting an etiological role of this gene in AD. SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which exhibits a protective role in AD pathogenesis through regulation of endocytic function and amyloid β (Aβ) metabolism. Despite its importance in AD pathogenesis, our knowledge of how SORLA is regulated by intracellular signaling molecules and the relevance of this regulation to AD is surprisingly scarce. In our preliminary studies, we identified a novel interaction between SORLA and βarrestin2 (βARR2), a multifunctional trafficking/signaling adaptor that is potentially involved in AD. Our preliminary data suggest that βARR2 disrupts retromer-mediated retrograde transport of SORLA and reduces SORLA stability. Furthermore, we found a significant increase in the SORLA-βARR2 interaction, which correlates with a decrease in the SORLA-retromer interaction, in postmortem brain tissues of AD subjects when compared to controls. Therefore, we discovered a novel βARR2-dependent regulation of SORLA trafficking and stability that is relevant to AD. In this proposal, we will determine the pathophysiological significance and underlying mechanism of this novel regulation and use preclinical tests to explore its potential as a therapeutic target for AD. In Aim 1, we will determine how βARR2 alters SORLA trafficking and stability to disrupt the endosome network and Aβ metabolism. In Aim 2, we will test how this βARR2-dependent regulation of SORLA is modulated by intracellular signaling. In Aim 3, we will explore the therapeutic potential of targeting this novel regulatory pathway in ameliorating AD-related deficits using animal models.
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