Exosome reduction invivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease

Michael B. Dinkins, Somsankar Dasgupta, Guanghu Wang, Gu Zhu, Erhard Bieberich

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

We present evidence here that exosomes stimulate aggregation of amyloid beta (Aβ)1-42 invitro and invivo and interfere with uptake of Aβ by primary cultured astrocytes and microglia invitro. Exosome secretion is prevented by the inhibition of neutral sphingomyelinase 2 (nSMase2), a key regulatory enzyme generating ceramide from sphingomyelin, with GW4869. Using the 5XFAD mouse, we show that intraperitoneal injection of GW4869 reduces the levels of brain and serum exosomes, brain ceramide, and Aβ1-42 plaque load. Reduction of total Aβ1-42 as well as number of plaques in brain sections was significantly greater (40% reduction) in male than female mice. Our results suggest that GW4869 reduces amyloid plaque formation invivo by preventing exosome secretion and identifies nSMase2 as a potential drug target in AD by interfering with exosome secretion.

Original languageEnglish (US)
Pages (from-to)1792-1800
Number of pages9
JournalNeurobiology of Aging
Volume35
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • Alzheimer's disease
  • Amyloid beta
  • Astrocytes
  • Exosomes
  • GW4869
  • Neutral sphingomyelinase
  • Primary culture

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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