Intracellular tracing of amyloid vaccines through direct fluorescent labelling

Abstract Alzheimer’s disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migrator...

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Autores principales:	Matthew Mold, Manpreet Kumar, Ambreen Mirza, Emma Shardlow, Christopher Exley
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8b074227a314421a9bdb4071a5bde60f
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spelling	oai:doaj.org-article:8b074227a314421a9bdb4071a5bde60f2021-12-02T15:08:44ZIntracellular tracing of amyloid vaccines through direct fluorescent labelling10.1038/s41598-018-20845-92045-2322https://doaj.org/article/8b074227a314421a9bdb4071a5bde60f2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20845-9https://doaj.org/toc/2045-2322Abstract Alzheimer’s disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation. However, the intrinsic phagocytic properties of such cells have pre-disposed them to internalise misfolded amyloidogenic peptides that could act as seeds capable of nucleating amyloid formation in the brain. Mechanisms governing the cellular fate of amyloid therefore, may prove to be key in the development of future vaccination regimes. Herein, we have developed unequivocal and direct conformation-sensitive fluorescent molecular probes that reveal the intracytoplasmic and intranuclear persistence of amyloid in a monocytic T helper 1 (THP-1) cell line. Use of the pathogenic Aβ42 species as a model antigen in simulated vaccine formulations suggested differing mechanisms of cellular internalisation, in which fibrillar amyloid evaded lysosomal capture, even when co-deposited on particulate adjuvant materials. Taken collectively, direct fluorescent labelling of antigen-adjuvant complexes may serve as critical tools in understanding subsequent immunopotentiation in vaccines directed against amyloidosis and wider dementia.Matthew MoldManpreet KumarAmbreen MirzaEmma ShardlowChristopher ExleyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew Mold Manpreet Kumar Ambreen Mirza Emma Shardlow Christopher Exley Intracellular tracing of amyloid vaccines through direct fluorescent labelling
description	Abstract Alzheimer’s disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation. However, the intrinsic phagocytic properties of such cells have pre-disposed them to internalise misfolded amyloidogenic peptides that could act as seeds capable of nucleating amyloid formation in the brain. Mechanisms governing the cellular fate of amyloid therefore, may prove to be key in the development of future vaccination regimes. Herein, we have developed unequivocal and direct conformation-sensitive fluorescent molecular probes that reveal the intracytoplasmic and intranuclear persistence of amyloid in a monocytic T helper 1 (THP-1) cell line. Use of the pathogenic Aβ42 species as a model antigen in simulated vaccine formulations suggested differing mechanisms of cellular internalisation, in which fibrillar amyloid evaded lysosomal capture, even when co-deposited on particulate adjuvant materials. Taken collectively, direct fluorescent labelling of antigen-adjuvant complexes may serve as critical tools in understanding subsequent immunopotentiation in vaccines directed against amyloidosis and wider dementia.
format	article
author	Matthew Mold Manpreet Kumar Ambreen Mirza Emma Shardlow Christopher Exley
author_facet	Matthew Mold Manpreet Kumar Ambreen Mirza Emma Shardlow Christopher Exley
author_sort	Matthew Mold
title	Intracellular tracing of amyloid vaccines through direct fluorescent labelling
title_short	Intracellular tracing of amyloid vaccines through direct fluorescent labelling
title_full	Intracellular tracing of amyloid vaccines through direct fluorescent labelling
title_fullStr	Intracellular tracing of amyloid vaccines through direct fluorescent labelling
title_full_unstemmed	Intracellular tracing of amyloid vaccines through direct fluorescent labelling
title_sort	intracellular tracing of amyloid vaccines through direct fluorescent labelling
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/8b074227a314421a9bdb4071a5bde60f
work_keys_str_mv	AT matthewmold intracellulartracingofamyloidvaccinesthroughdirectfluorescentlabelling AT manpreetkumar intracellulartracingofamyloidvaccinesthroughdirectfluorescentlabelling AT ambreenmirza intracellulartracingofamyloidvaccinesthroughdirectfluorescentlabelling AT emmashardlow intracellulartracingofamyloidvaccinesthroughdirectfluorescentlabelling AT christopherexley intracellulartracingofamyloidvaccinesthroughdirectfluorescentlabelling
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Intracellular tracing of amyloid vaccines through direct fluorescent labelling

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