Abstract 1451 Alzheimer's disease is likely a lipid-disorder complication: An example of functional lipidomics research

Sulfatide, a class of sphingolipids, is a major lipid component in the nervous system, predominantly present in the extracellular leaflet of myelin sheath and specifically synthesized by cerebroside sulfotransferase (CST) in oligodendrocytes in the CNS. We and many other laboratories have revealed that brain sulfatide content is specifically and dramatically reduced at the earliest clinically recognizable stages of Alzheimer's disease (AD) and in all AD mouse models examined (e.g., PMID: 12358786; PMID: 12501252; PMID: 18762354). Our recent studies using an adult-onset sulfatide-deficit mouse model have uncovered that CNS sulfatide deficiency is sufficient to activate disease-associated microglia and astrocytes, leading to chronic AD-like neuroinflammation and cognitive impairment (PMID: 34526055). We also demonstrated that adult-onset sulfatide deficiency led to many other AD-like pathologies, including brain ventricular enlargement, bladder enlargement, and marked metabolic disruption in a sex-dependent manner (PMID: 36613677; PMID: 37445661; PMID: 37239102; PMID: 37478300; doi.org/10.1002/glia.24423). In the current presentation, the sulfatide deficiency-induced AD-like phenotypes will be outlined and, selectively, sulfatide deficiency-induced phosphatidic acid reduction and its sequela will be discussed in some details. We believe CNS sulfatide deficiency plays a crucial role in AD pathogenesis. NIH (RF1 AG061872, RF1 AG061729, U54 NS110435, U19 AG069701, P30 AG066546, P30 AG013319, and P30 AG044271) and Cure Alz Fund.