Cell Biology of Presenilin 1 and Associated Proteins

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DESCRIPTION (provided by applicant): Cerebral deposition of beta-amyloid peptides (ABeta) is one of the pathological hallmarks of Alzheimer's disease. AB is generated by sequential proteolysis of amyloid precursor protein (APP) by BACE1 and gamma-secretase. gamma-secretase is a multimeric protein complex made of four main subunits, namely PS1 (or PS2), nicastrin, PEN2 and APH-1, and a few regulatory subunits including CD147 and p23 (also referred to asTMP21). PS1 is thought to function as the catalytic subunit of gamma-secretase complex. Post-translational maturation and stability of the four core subunits of gamma-secretase are mutually regulated, and each of them is indispensable for functional enzyme activity. On the other hand, diminution of CD147 or p23 expression increases AB production, suggesting that these proteins negatively regulate gamma-secretase processing of APP. The specific mechanisms by which p23 modulates gamma-secretase cleavage of APP remain undetermined. Studies outlined in this proposal address the function of p23 in trafficking and gamma-secretase processing of APP in cultured cells and in mouse brains Specifically, we propose to elucidate the functional interaction between p23 and gamma-secretase subunits so that we can better understand the mechanisms by which p23 negatively regulates ABeta production. We will define the structural domains essential for p23's influence on APP trafficking and ABeta production, and investigate p23 modulation of ABeta deposition using p23 transgenic mice and p23 conditional knockout mice. Finally, we will investigate the details on p23's role in secretory and endocytic trafficking of APP and examine the relationship between Golgi morphology and AB production. Our investigation uses a combination of biochemical, molecular and cell biology techniques to accomplish the following specific aims. Aim 1: To study the functional interaction between p23 and gamma-secretase. Aim 2: To investigate p23 regulation of ABeta production and deposition in mouse brain. Aim 3: To determine the mechanisms linking p23 function with APP trafficking and gamma-secretase processing. Our studies address issues that are central to molecular Alzheimer's disease pathogenesis. We seek to investigate a novel aspect of gamma-secretase modulation by p23 that impacts on ABeta production. Our studies have the potential to uncover significant insights on p23 regulation of APP trafficking and ABeta production, and may lead to the development of p23-based novel therapeutic strategies aimed reducing ABeta burden by selective inactivation of gamma-secretase function in APP processing.