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Neurobiol Aging. 2014 Aug;35(8):1792-800. doi: 10.1016/j.neurobiolaging.2014.02.012. Epub 2014 Feb 15.

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

Author information

  • 1Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA.
  • 2Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA. Electronic address: ebieberich@gmail.com.

Abstract

We present evidence here that exosomes stimulate aggregation of amyloid beta (Aβ)1-42 in vitro and in vivo and interfere with uptake of Aβ by primary cultured astrocytes and microglia in vitro. 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 in vivo by preventing exosome secretion and identifies nSMase2 as a potential drug target in AD by interfering with exosome secretion.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

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

PMID:
24650793
[PubMed - indexed for MEDLINE]
PMCID:
PMC4035236
Free PMC Article
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