Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice

ABSTRACT Aggregation of misfolded host proteins in the central nervous system is believed to be important in the pathogenic process in several neurodegenerative diseases of humans, including prion diseases, Alzheimer's disease, and Parkinson's disease. In these diseases, protein misfolding...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Bruce Chesebro, James Striebel, Alejandra Rangel, Katie Phillips, Andrew Hughson, Byron Caughey, Brent Race
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/da548ec526a5483a8b786727f710eeb9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:da548ec526a5483a8b786727f710eeb9
record_format	dspace
spelling	oai:doaj.org-article:da548ec526a5483a8b786727f710eeb92021-11-15T15:41:30ZEarly Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice10.1128/mBio.01419-152150-7511https://doaj.org/article/da548ec526a5483a8b786727f710eeb92015-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01419-15https://doaj.org/toc/2150-7511ABSTRACT Aggregation of misfolded host proteins in the central nervous system is believed to be important in the pathogenic process in several neurodegenerative diseases of humans, including prion diseases, Alzheimer's disease, and Parkinson's disease. In these diseases, protein misfolding and aggregation appear to expand through a process of seeded polymerization. Prion diseases occur in both humans and animals and are experimentally transmissible orally or by injection, thus providing a controllable model of other neurodegenerative protein misfolding diseases. In rodents and ruminants, prion disease has a slow course, lasting months to years. Although prion infectivity has been detected in brain tissue at 3 to 4 weeks postinfection (p.i.), the details of early prion replication in the brain are not well understood. Here we studied the localization and quantitation of PrPSc generation in vivo starting at 30 min postmicroinjection of scrapie into the brain. In C57BL mice at 3 days p.i., generation of new PrPSc was detected by immunohistochemistry and immunoblot assays, and at 7 days p.i., new generation was confirmed by real-time quaking-induced conversion assay. The main site of new PrPSc generation was near the outer basement membrane of small and medium blood vessels. The finding and localization of replication at this site so early after injection have not been reported previously. This predominantly perivascular location suggested that structural components of the blood vessel basement membrane or perivascular astrocytes might act as cofactors in the initial generation of PrPSc. The location of PrPSc replication at the basement membrane also implies a role for the brain interstitial fluid drainage in the early infection process. IMPORTANCE Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and prion diseases, of humans are characterized by misfolding and aggregation of certain proteins, resulting in the destruction of brain tissue. In these diseases, the damage process spreads progressively within the central nervous system, but only prion diseases are known to be transmissible between individuals. Here we used microinjection of infectious prion protein (PrPSc) into the mouse brain to model early events of iatrogenic prion transmission via surgical instruments or tissue grafts. At 3 and 7 days postinjection, we detected the generation of new PrPSc, mostly on the outer walls of blood vessels near the injection site. This location and very early replication were surprising and unique. Perivascular prion replication suggested the transport of injected PrPSc via brain interstitial fluid to the basement membranes of blood vessels, where interactions with possible cofactors made by astrocytes or endothelia might facilitate the earliest cycles of prion infection.Bruce ChesebroJames StriebelAlejandra RangelKatie PhillipsAndrew HughsonByron CaugheyBrent RaceAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 5 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Bruce Chesebro James Striebel Alejandra Rangel Katie Phillips Andrew Hughson Byron Caughey Brent Race Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
description	ABSTRACT Aggregation of misfolded host proteins in the central nervous system is believed to be important in the pathogenic process in several neurodegenerative diseases of humans, including prion diseases, Alzheimer's disease, and Parkinson's disease. In these diseases, protein misfolding and aggregation appear to expand through a process of seeded polymerization. Prion diseases occur in both humans and animals and are experimentally transmissible orally or by injection, thus providing a controllable model of other neurodegenerative protein misfolding diseases. In rodents and ruminants, prion disease has a slow course, lasting months to years. Although prion infectivity has been detected in brain tissue at 3 to 4 weeks postinfection (p.i.), the details of early prion replication in the brain are not well understood. Here we studied the localization and quantitation of PrPSc generation in vivo starting at 30 min postmicroinjection of scrapie into the brain. In C57BL mice at 3 days p.i., generation of new PrPSc was detected by immunohistochemistry and immunoblot assays, and at 7 days p.i., new generation was confirmed by real-time quaking-induced conversion assay. The main site of new PrPSc generation was near the outer basement membrane of small and medium blood vessels. The finding and localization of replication at this site so early after injection have not been reported previously. This predominantly perivascular location suggested that structural components of the blood vessel basement membrane or perivascular astrocytes might act as cofactors in the initial generation of PrPSc. The location of PrPSc replication at the basement membrane also implies a role for the brain interstitial fluid drainage in the early infection process. IMPORTANCE Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and prion diseases, of humans are characterized by misfolding and aggregation of certain proteins, resulting in the destruction of brain tissue. In these diseases, the damage process spreads progressively within the central nervous system, but only prion diseases are known to be transmissible between individuals. Here we used microinjection of infectious prion protein (PrPSc) into the mouse brain to model early events of iatrogenic prion transmission via surgical instruments or tissue grafts. At 3 and 7 days postinjection, we detected the generation of new PrPSc, mostly on the outer walls of blood vessels near the injection site. This location and very early replication were surprising and unique. Perivascular prion replication suggested the transport of injected PrPSc via brain interstitial fluid to the basement membranes of blood vessels, where interactions with possible cofactors made by astrocytes or endothelia might facilitate the earliest cycles of prion infection.
format	article
author	Bruce Chesebro James Striebel Alejandra Rangel Katie Phillips Andrew Hughson Byron Caughey Brent Race
author_facet	Bruce Chesebro James Striebel Alejandra Rangel Katie Phillips Andrew Hughson Byron Caughey Brent Race
author_sort	Bruce Chesebro
title	Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
title_short	Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
title_full	Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
title_fullStr	Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
title_full_unstemmed	Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
title_sort	early generation of new prpsc on blood vessels after brain microinjection of scrapie in mice
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/da548ec526a5483a8b786727f710eeb9
work_keys_str_mv	AT brucechesebro earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT jamesstriebel earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT alejandrarangel earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT katiephillips earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT andrewhughson earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT byroncaughey earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice AT brentrace earlygenerationofnewprpsconbloodvesselsafterbrainmicroinjectionofscrapieinmice
_version_	1718427734116401152

Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice

Ejemplares similares