SULFATIDE DEFICIENCY: A NOVEL MECHANISM LEADING TO REACTIVE ASTROGLIOSIS IN AGING AND ALZHEIMER'S DISEASE
Aging is the greatest known risk factor for Alzheimer's disease (AD), the most common cause of dementia inolder individuals. However, effective AD therapies remain elusive, which underscores the need to betterunderstand disease etiology and its co-occurrence with advanced age. The apolipoprotein E4 (apoE4) allele isthe strongest genetic risk factor for late-onset AD and it is associated with decreased lifespan. The apoEprotein is crucial to lipid homeostasis through its regulation of cholesterol, triglyceride and phospholipidmetabolism in the blood and the brain. Sulfatide is a key component of the myelin sheath, and is metabolizedthrough apoE transport. Previous studies from our lab and others revealed a strong association betweensulfatide deficiency, a specific metabolic abnormality, and astrogliosis, a pathologic reaction related toneuroinflammation. For example, sulfatide deficiency and astrogliosis both are induced by aging, in apoE4carriers, and under AD conditions. Our preliminary studies using sulfatide-depleted mice showed (1) markedastrogliosis within myelin regions; (2) astrogliosis independent of microgliosis; (3) marked upregulation ofphosphorylated (activated) STAT3 and (4) a significant upregulation of astrocytic LDL receptor-related protein1 (LRP1). Finally, multiple studies have consistently demonstrated that sulfatide recruits and directly interactswith laminin, an extracellular matrix (ECM) protein. Our novel findings led us to hypothesize that aberrant lipidmetabolism and sulfatide deficiency causes fibrous astrogliosis via LRP1- and/or ECM/integrin-mediatedSTAT3 activation. To test this central hypothesis, we propose three Specific Aims: 1) To examine the role ofsulfatide deficiency on development of fibrous astrogliosis (independently of microgliosis) and cognitiveimpairment, using a novel oligodendrocyte-specific sulfatide-depleted mouse model; 2) To determine whetherastrogliosis caused by sulfatide deficiency is prevented/ameliorated by knocking down astrocytic STAT3 andLRP1 expression; and 3) To determine if replenishing brain sulfatide content ameliorates or preventsastrogliosis and cognitive impairment in mouse models of AD, normal aging, and apoE4. To the best of ourknowledge, the proposed research (in response to PAR-17-031, ?Role of Age-Associated MetabolicChanges in Alzheimer's Disease?) is the first to study the potential role of sulfatide deficiency in astrogliosisand neuroinflammation, and to examine the molecular mechanism by which sulfatide deficiency promotesneurodegeneration in AD. If our hypothesis is borne out, this work also will provide proof-of-concept to supportthe development of novel sulfatide-based therapeutic strategies seeking to treat AD and other sulfatidedeficiency-associated pathologic conditions.