Non‐amyloid and amyloid prion protein deposits in prion‐infected mice differ in blockage of interstitial brain fluid

Rangel, Alejandra; Race, Brent; Striebel, James F.; Chesebro, Bruce

doi:10.1111/j.1365-2990.2012.01303.x

Cited by 10 publications

(19 citation statements)

References 34 publications

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“…This PrPSc was not only detected in the NT wound but also was seen surrounding numerous nearby small blood vessels, as well as within the adjacent corpus callosum white matter. These locations are known to be areas of drainage of CNS solutes in the brain ISF and are similar to the areas where we and others previously detected an ISF tracer, fluorescein isothiocyanate-ovalbumin, after similar microinjections ( 22 , 30 , 31 ).…”

Section: Discussionsupporting

confidence: 84%

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

Chesebro¹,

Striebel²,

Rangel³

et al. 2015

mBio

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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.

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Section: Discussionsupporting

confidence: 84%

“…1A and C ). These perivascular sites and the white matter tracts are known sites of drainage of brain ISF ( 22 ). Thus, the injected PrPSc appeared to be rapidly collected by the ISF system for removal from the brain along with other solutes.…”

Section: Resultsmentioning

confidence: 99%

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

Chesebro¹,

Striebel²,

Rangel³

et al. 2015

mBio

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“…In our previous work, tracer was detectable on blood vessels at 30 min, much reduced at 7 hours and almost completely gone by 24 hours [27]. The present study provides quantitative data on specificity of the ISF tracer FITC-OVA for capillaries, arteries and veins.…”

Section: Discussionsupporting

confidence: 62%

Unusual cerebral vascular prion protein amyloid distribution in scrapie-infected transgenic mice expressing anchorless prion protein

Rangel

Race

Striebel

et al. 2013

acta neuropathol commun

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BackgroundIn some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy. Small diffusible precursors of PrPres amyloid might flow with brain interstitial fluid (ISF), possibly accounting for the perivascular and intravascular distribution of PrPres amyloid. We previously reported that PrPres amyloid in scrapie-infected transgenic mice appeared to delay clearance of microinjected brain ISF tracer molecules.ResultsHere we studied distribution of PrPres amyloid on capillaries, arteries and veins to test whether vascular specificity of PrPres corresponded to distribution of ISF tracer molecules. To distinguish PrPres-positive arteries from veins and capillaries, scrapie-infected mouse brains were studied by immunodetection of alpha smooth muscle actin. ISF was studied using fluorescein-labeled ovalbumin microinjected into brain as a tracer. In infected preclinical or clinical mice, PrPres was found mostly on capillaries (73-78%). Lower levels were found on arteries (11-14%) and veins (11-13%). Compared to PrPres, ISF tracer was found at higher levels on capillaries (96-97%), and the remaining tracer was found at a skewed ratio of 4 to 1 on arteries and veins respectively.ConclusionsPrPres association with blood vessels suggested that ISF flow might transport diffusible PrPres precursor molecules to perivascular sites. However, the different vascular specificity of PrPres and ISF tracer indicated that ISF flow did not alone control PrPres dissemination. Possibly blood vessel basement membrane (BM) components, such as glucosaminoglycans, might concentrate small PrPres aggregates and serve as scaffolds for PrP conversion on multiple vessel types.

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“…A progressive involvement of basement membranes located towards the lumen of arterioles and the subsequent assembly of fibrils within basement membranes precedes replacement of the walls of vessels by amyloid. In contrast to PrP d attached to membranes, aggregates of anchorless PrP d that accumulate in basement membranes of arterioles do delay the drainage of ISF . High concentrations of PrP d in the extracellular fluid may in turn promote further PEFA‐CAA.…”

Section: Pefa and The Transmissible Spongiform Encephalopathies Or Prmentioning

confidence: 99%

Review: Cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy

Carare

Hawkes

Jeffrey

et al. 2013

Neuropathology Appl Neurobio

178

182

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Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aβ), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aβ (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

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Non‐amyloid and amyloid prion protein deposits in prion‐infected mice differ in blockage of interstitial brain fluid

Cited by 10 publications

References 34 publications

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

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

Unusual cerebral vascular prion protein amyloid distribution in scrapie-infected transgenic mice expressing anchorless prion protein

Review: Cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy

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