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 the metabolism of various lipids in blood and the
brain. Sulfatide (ST) is a key component of myelin and is metabolized through APOE transport. Previous
studies from our lab and others revealed a strong association between ST deficiency, a specific metabolic
abnormality, and astrogliosis, a pathologic reaction related to neuroinflammation. For example, ST deficiency
and astrogliosis both are induced by aging, in APOE4 carriers, and under AD conditions. Our preliminary
studies using ST deficiency 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 oncostatin M receptor (OSMR), which is known to interact with ST. Finally, multiple
studies have consistently demonstrated that ST recruits and directly interacts with laminin, an extracellular
matrix (ECM) protein. Our novel findings led us to hypothesize that ST loss is directly sensed by astrocytic
processes through a mechanism that involves a disruption of ST-ECM-integrin/OSMR interactions that lead to
STAT3 activation. To test this central hypothesis, we propose three Specific Aims: 1) To examine the effects
of brain ST deficiency on astrocyte reactivity, neuroinflammation, and cognitive function using a novel inducible
mouse model of conditional ST deficiency; 2) To unravel the molecular mechanism(s) underlying ST
deficiency-induced astrogliosis; and 3) To determine if restoring brain ST content ameliorates astrogliosis,
neuroinflammation, and cognitive impairment in the context of AD and aging. 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 ST deficiency in astrogliosis and
neuroinflammation, and to examine the molecular mechanism by which ST 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 ST-based therapeutic strategies seeking to treat AD and other ST deficiency-
associated pathologic conditions.