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

Alejandra Rangel,James Striebel,Bruce Chesebro,Mikael Klingeborn,Brent Race

doi:10.1186/2051-5960-1-25

Abstract

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.

Highlights

In some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy
In leptomeningeal vessels of Alzheimer’s disease (AD) patients the ratio of Aβ-positive arteries to veins was 4.5 to 1 [21]. This Aβ amyloid distribution mirrored the pattern of the bulk flow of brain interstitial fluid (ISF) tracers which appear to drain from the brain in perivascular spaces of arteries more than veins [22,23], suggesting that ISF flow might play a role in the vascular distribution of amyloid in AD [24]
Cerebral vascular distribution of PrPres in scrapie-infected Tg44+/+ mice To identify the blood vessel types associated with PrPres amyloid plaques in brain, scrapie-infected Tg44+/+ mice were studied during early clinical disease from 250–280 dpi

Summary

Introduction

In some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy. We generated transgenic Tg44 mice, which express only the anchorless form of PrP, and in these mice scrapie-infection results in an unusual type of slow fatal prion brain disease distinguished by widespread deposition of PrPres amyloid in the central nervous system [10] and in extraneural sites such as heart, brown fat, white fat and colon [11,12]. The perivascular PrPres amyloid deposition and associated pathology seen in scrapie-infected Tg44 mice is similar to cerebral amyloid angiopathy (CAA) seen in several familial brain amyloid diseases involving mutant proteins or peptides (for review see [13]). In the case of prion diseases, PrP mutations including Y145X, Q160X, Y163X and Y226X [13,14,15,16] have been associated with development of CAA with perivascular PrPres amyloid, and all these mutations give rise to truncated PrP molecules which lack the glycophosphatidylinositol (GPI) anchor. This Aβ amyloid distribution mirrored the pattern of the bulk flow of brain interstitial fluid (ISF) tracers which appear to drain from the brain in perivascular spaces of arteries more than veins [22,23], suggesting that ISF flow might play a role in the vascular distribution of amyloid in AD [24]

Methods

Results

Discussion

Conclusion