The role of tetraspanin-regulated endolysosomal trafficking in Alzheimer's Disease - Although the accumulation of Aβ and subsequent chronic inflammation and neuronal dysfunction likely contribute to the development of Alzheimer’s disease (AD) pathology and clinical manifestation, the mechanisms for AD initiation and progression in sporadic, late-onset cases remain unclear. An abundance of pathological and genetic evidence points towards a role of the endolysomal network and its effects on APP trafficking and processing as a potential initiator of the disease. We recently found that tetraspanin CD151 restrains the releases of i) APP, ii) α-secretase, and iii) pro-inflammatory molecules. Our recent studies also show that CD151 sustains proper structure and function of endolysosomes, e.g., supporting proper turnover of proteins in endolysosomes. These observations underline a putative mechanistic connection between dysregulated endolysosome function, resulting from the diminished CD151 level in inflammation and aging, and abnormal processing of APP, leading to chronic inflammation and AD. This notion forms the basis of our hypothesis for this research project, i.e., CD151-dependent endolysosome trafficking is required for proper degradation and limited release of APP. The goal of this project is to understand the mechanistic roles of CD151-regulated endolysosomal proteolysis in the pathogenesis of AD. Specifically, we will assess both in vitro and in vivo effects of CD151 removal on the i) endolysosomal trafficking and/or processing of APP and/or its relevant secretases, ii) secretion of pro-inflammatory molecules, and iii) AD-related pathological and behavior changes. From these in-depth mechanistic studies, we will understand if and how CD151-dependent regulation of endolysosomes is important for the progression of AD, likely establish a novel paradigm between molecular identity of endolysosomes and proteolytic determination of APP, and possibly delineate the molecular switch that governs the Aβ deposition in brain. At the end of this project, we will develop an integrated understanding of the unique features of endolysosome and tetraspanin CD151 in the pathogenesis of AD, which will ultimately lead to the development of therapeutic strategies against AD.
