A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer's disease.

Defective immune cell-mediated clearance of amyloid-beta (Aβ) and Aβ-associated inflammatory activation of immune cells are key contributors in pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms remain elusive. Shank-associated RH domain-interacting protein (SHARPIN) is a critical regulator of inflammatory response. Using in vitro cultures of THP-1-derived macrophages exposed to Aβ and AD patient-derived macrophages, we demonstrate the role of SHARPIN as an obligate regulator of Aβ phagocytosis and inflammation in macrophages. Specifically, Aβ-stimulated SHARPIN in THP-1 macrophages promoted Aβ phagocytosis and expression of proinflammatory markers. In addition, Aβ-stimulated SHARPIN in macrophages promoted neuronal cell-death in differentiated SHSY5Y neurons. Furthermore, we report a novel regulatory link between SHARPIN and the NLRP3 inflammasome in response to Aβ in THP-1 macrophages. In line with our in vitro observations, a strong positive association was demonstrated between levels of Aβ in blood plasma of mild cognitive impairment and AD patients with SHARPIN expression in macrophages obtained from respective patient-derived peripheral blood mononuclear cells. Together, our findings show SHARPIN as a critical determinant in mediating macrophage response to Aβ and pathogenesis of AD.