The parent grant is to understand the roles of hepatic immunoproteasome in inflammatory metabolic diseases. The central hypothesis of the parent grant is that hepatic immunoproteasome induces metabolic reprogramming by selective digestion of proteins involved in metabolic homeostasis and anti-inflammation. As consequences, the immunoproteasome plays important roles in the development of metabolic abnormalities. Successful outcomes of the parent grant are anticipated to define the immunoproteasome as a promising therapeutic target for inflammatory metabolic diseases, such as non-alcoholic fatty liver (NAFLD), non-alcoholic steatohepatitis, and obesity. This supplemental grant is to explore a novel direction of research that links hepatic immunoproteasome as a therapeutic target for Alzheimer’s disease (AD). This direction of research has been developed based on our preliminary work in characterizing the liver-specific mouse model for the immunoproteasome. We found that the liver immunoproteasome is a key factor not only for liver inflammation but also brain inflammation in metabolically stressed mouse. The liver is the organ most susceptible to infection, toxicity and stress, and an important organ for AD development. NAFLD is prevalent in AD patients. NAFLD induced advanced pathological signs of AD in wild type and AD mouse model. The rising epidemic of NAFLD is associated with cognitive decline and is considered as a major risk factor for AD. Therefore, effective treatments for NAFLD are anticipated to ameliorate AD pathology. There is not yet an effective treatment for NAFLD. Our preliminary study showed that depletion of the immunoproteasome in the liver significantly reduces brain inflammation. Furthermore, depletion of hepatic immunoproteasome improved metabolism protecting the mice from obesity, insulin resistance and steatosis. Based on these results, we hypothesize that the immunoproteasome in the liver is a key mediator of metabolic stress for systemic inflammation that contributes to brain inflammation and amyloid pathology. Whether the liver immunoproteasome is a promising therapeutic target for HFD-induced metabolic diseases and AD has never been explored. The liver immunoproteasome shifts the liver capacity to digest many key factors involved in inflammation, transcription, and signal transduction. We hypothesize that the change in the proteolytic capacity alters the ability of the liver to take up and clear up Aβ. We propose that targeting the liver immunoproteasome is a promising strategy to ameliorate AD. In the supplemental grant, we will determine the effects of hepatic immunoproteasome depletion on AD pathology using AD mouse models. Successful outcomes will establish a new research direction toward peripheral proteolysis regulation of AD pathology. Establishing the roles of the liver immunoproteasome in amyloid pathology will advance the knowledge on AD development and provide new insights into therapeutics for AD.