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

ABSTRACT: We present evidence here that exosomes stimulate aggregation of amyloid beta (A?)1-42 in vitro and in vivo and interfere with uptake of A? 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 A?1-42 plaque load. Reduction of total A?1-42 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.

SUBMITTER: Dinkins MB

PROVIDER: S-EPMC4035236 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Dinkins Michael B MB Dasgupta Somsankar S Wang Guanghu G Zhu Gu G Bieberich Erhard E

Neurobiology of aging 20140215 8

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 ...[more]

PMID: 24650793

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