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

Physiology

Producción científica: Article › revisión exhaustiva

431 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1792-1800
Número de páginas	9
Publicación	Neurobiology of Aging
Volumen	35
N.º	8
DOI	https://doi.org/10.1016/j.neurobiolaging.2014.02.012
Estado	Published - ago 2014

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)
National Institute on Aging	R01AG034389

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.",

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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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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

Resumen

Nota bibliográfica

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ASJC Scopus subject areas

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