Function of Ceramide in Extracellular Vesicle-Mediated Neurodegenerative Disease

Alzheimer’s disease (AD) is characterized by the buildup of Amyloid β (Aβ) peptide and hyperphosphorylated tau, both of which drive neurodegeneration and cognitive decline. There is no clarity as to how Aβ and tau damage neurons. A critical knowledge gap and barrier to progress, is the lack of a thorough understanding of factors that may enhance neurotoxicity of Aβ and tau. Our previous studies have shown that in response to Aβ produced by neurons, astrocytes secrete extracellular vesicles (EVs), or “astrosomes”, which are enriched with the sphingolipid ceramide and bind to Aβ. We discovered that these Aβ-associated astrosomes (AAAs) induce neurodegeneration in AD, which can be prevented by inhibition or deficiency of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates ceramide by hydrolysis of the membrane lipid sphingomyelin. Therefore, we hypothesize that ceramide is a key factor mediating AAA formation and neurotoxicity and preventing AAA formation and neurotoxicity by inhibiting ceramide generation is a novel strategy for AD therapy. Our studies showed that improvement of AD pathology and cognition by nSMase2 inhibition or deficiency were only detected in male mice, indicating that additional enzymes in ceramide metabolism contribute to AAA formation and neurotoxicity independently of nSMase2. Our goal is to define enzymes in ceramide metabolism underlying a sex-specific dimorphism in AAA formation and neurotoxicity and develop novel drug approaches that are effective in both sexes. In our Specific Aims, we will use novel and innovative approaches, particularly using new mouse models, analytical techniques, and drugs to understand the sex-specific AAA formation and target ceramide metabolism to interfere with the formation of AAAs in astrocytes (Specific Aim 1) and their neurotoxicity in neurons (Specific Aim 2) to prevent AD pathology and improve cognition independent of sex (Specific Aim 3). The impact of our study on public health is to generate knowledge that leads to the development of novel AD therapies. While the primary focus of our study is ceramide and Aβ in AAAs, some identified factors may also be applicable to the neurotoxicity of tau.