title: Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer's Disease Pathology and Improves Cognition in the 5XFAD Mouse.
abstract: Recent evidence implicates exosomes in the aggregation of Aβ and spreading of tau in Alzheimer's disease. In neural cells, exosome formation can be blocked by inhibition or silencing of neutral sphingomyelinase-2 (nSMase2). We generated genetically nSMase2-deficient 5XFAD mice (fro;5XFAD) to assess AD-related pathology in a mouse model with consistently reduced ceramide generation. We conducted in vitro assays to assess Aβ42 aggregation and glial clearance with and without exosomes isolated by ultracentrifugation and determined exosome-induced amyloid aggregation by particle counting. We analyzed brain exosome content, amyloid plaque formation, neuronal degeneration, sphingolipid, Aβ42 and phospho-tau levels, and memory-related behaviors in 5XFAD versus fro;5XFAD mice using contextual and cued fear conditioning. Astrocyte-derived exosomes accelerated aggregation of Aβ42 and blocked glial clearance of Aβ42 in vitro Aβ42 aggregates were colocalized with extracellular ceramide in vitro using a bifunctional ceramide analog preloaded into exosomes and in vivo using anticeramide IgG, implicating ceramide-enriched exosomes in plaque formation. Compared with 5XFAD mice, the fro;5XFAD mice had reduced brain exosomes, ceramide levels, serum anticeramide IgG, glial activation, total Aβ42 and plaque burden, tau phosphorylation, and improved cognition in a fear-conditioned learning task. Ceramide-enriched exosomes appear to exacerbate AD-related brain pathology by promoting the aggregation of Aβ. Reduction of exosome secretion by nSMase2 loss of function improves pathology and cognition in the 5XFAD mouse model.
  
  
  
  We present for the first time evidence, using Alzheimer's disease (AD) model mice deficient in neural exosome secretion due to lack of neutral sphingomyelinase-2 function, that ceramide-enriched exosomes exacerbate AD-related pathologies and cognitive deficits. Our results provide rationale to pursue a means of inhibiting exosome secretion as a potential therapy for individuals at risk for developing AD.
authors.affiliation: Department of Neuroscience and Regenerative Medicine.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dinkins
authors.affiliation: Department of Neuroscience and Regenerative Medicine.
authors.forename: John
authors.identifier: 0000-0001-6377-7894
authors.initials: J
authors.lastname: Enasko
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Caterina
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Department of Neuroscience and Regenerative Medicine.
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Regenerative Medicine.
authors.forename: Jina
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Cellular Biology and Anatomy, The Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Inas
authors.initials: I
authors.lastname: Helwa
authors.affiliation: Department of Cellular Biology and Anatomy, The Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.affiliation: Department of Neuroscience and Regenerative Medicine, ebieberich@augusta.edu.
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; C508853:PSEN1 protein, human; D053764:Presenilin-1; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase
keywords: 5XFAD; Alzheimer's; ceramide; exosomes; fear conditioning; sphingomyelinase