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

doi:10.1016/j.neurobiolaging.2014.02.012

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 journal › Article › peer-review

340 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 language	English (US)
Pages (from-to)	1792-1800
Number of pages	9
Journal	Neurobiology of Aging
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.neurobiolaging.2014.02.012
State	Published - Aug 2014
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

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10.1016/j.neurobiolaging.2014.02.012

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title = "Exosome reduction invivo 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 (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.",

keywords = "Alzheimer's disease, Amyloid beta, Astrocytes, Exosomes, GW4869, Neutral sphingomyelinase, Primary culture",

author = "Dinkins, {Michael B.} and Somsankar Dasgupta and Guanghu Wang and Gu Zhu and Erhard Bieberich",

note = "Funding Information: This work was funded by the National Institutes of Health R01-AG034389 to E.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank C. Wakade and J. Pihkala for additional technical assistance. They are grateful to Katarzyrna Pituch (supervisor Dr Irene Givogri), University of Illinois at Chicago, for assistance with the exosome isolation from brain. They thank the imaging core facility (under supervision of Drs Ana and Paul McNeil) for help with confocal microscopy. They also thank the Institute of Molecular Medicine and Genetics (Dr Lin Mei, director), Georgia Regents University, Augusta, GA, for institutional support. ",

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AU - Wang, Guanghu

AU - Zhu, Gu

AU - Bieberich, Erhard

N1 - Funding Information: This work was funded by the National Institutes of Health R01-AG034389 to E.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank C. Wakade and J. Pihkala for additional technical assistance. They are grateful to Katarzyrna Pituch (supervisor Dr Irene Givogri), University of Illinois at Chicago, for assistance with the exosome isolation from brain. They thank the imaging core facility (under supervision of Drs Ana and Paul McNeil) for help with confocal microscopy. They also thank the Institute of Molecular Medicine and Genetics (Dr Lin Mei, director), Georgia Regents University, Augusta, GA, for institutional support.

PY - 2014/8

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N2 - 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.

AB - 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.

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

Abstract

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