Project Summary Aging is the greatest known risk factor for Alzheimer's disease (AD), the most common cause of dementia in older individuals. However, effective AD therapies remain elusive, which underscores the need to better understand disease etiology and its co-occurrence with advanced age. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for late-onset AD and it is associated with decreased lifespan. The apoE protein is crucial to lipid homeostasis through its regulation of cholesterol, triglyceride and phospholipid metabolism in the blood and the brain. Sulfatide is a key component of the myelin sheath, and is metabolized through apoE transport. Previous studies from our lab and others revealed a strong association between sulfatide deficiency, a specific metabolic abnormality, and astrogliosis, a pathologic reaction related to neuroinflammation. For example, sulfatide deficiency and astrogliosis both are induced by aging, in apoE4 carriers, and under AD conditions. Our preliminary studies using sulfatide-depleted mice showed (1) marked astrogliosis within myelin regions; (2) astrogliosis independent of microgliosis; (3) marked upregulation of phosphorylated (activated) STAT3 and (4) a significant upregulation of astrocytic LDL receptor-related protein 1 (LRP1). Finally, multiple studies have consistently demonstrated that sulfatide recruits and directly interacts with laminin, an extracellular matrix (ECM) protein. Our novel findings led us to hypothesize that aberrant lipid metabolism and sulfatide deficiency causes fibrous astrogliosis via LRP1- and/or ECM/integrin-mediated STAT3 activation. To test this central hypothesis, we propose three Specific Aims: 1) To examine the role of sulfatide deficiency on development of fibrous astrogliosis (independently of microgliosis) and cognitive impairment, using a novel oligodendrocyte-specific sulfatide-depleted mouse model; 2) To determine whether astrogliosis caused by sulfatide deficiency is prevented/ameliorated by knocking down astrocytic STAT3 and LRP1 expression; and 3) To determine if replenishing brain sulfatide content ameliorates or prevents astrogliosis and cognitive impairment in mouse models of AD, normal aging, and apoE4. To the best of our knowledge, the proposed research (in response to PAR-17-031, ?Role of Age-Associated Metabolic Changes in Alzheimer's Disease?) is the first to study the potential role of sulfatide deficiency in astrogliosis and neuroinflammation, and to examine the molecular mechanism by which sulfatide deficiency promotes neurodegeneration in AD. If our hypothesis is borne out, this work also will provide proof-of-concept to support the development of novel sulfatide-based therapeutic strategies seeking to treat AD and other sulfatide deficiency-associated pathologic conditions.