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From: TSS ()
Subject: Prion-Induced Amyloid Heart Disease with High Blood Infectivity in Transgenic Mice
Date: July 6, 2006 at 1:59 pm PST

Prion-Induced Amyloid Heart Disease

with High Blood Infectivity in

Transgenic Mice

Matthew J. Trifilo,1 Tosh!taka Yajima,2 Yusu Gu,2 Nancy Dalton,2 Kirk L. Peterson,2

Richard E. Race,3 Kimberly Meade-White,3 John L. Portis,3 Eliezer Masliah,4

Kirk U. Knowlton,2* Bruce Chesebro,3* Michael B. A. Oldstone1*

We investigated extraneural manifestations in scrapie-infected transgenic mice expressing

prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and

heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily

detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious

scrapie in blood plasma exceeded 107 50% infectious doses per milliliter. The hearts of these

transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness

and cardiac disease.

In humans and animals, transmissible spongiform

encephalopathies (TSEs), or prion

diseases, cause neurodegeneration and death

following ingestion or experimental inoculation

of infected material. Prion diseases are

characterized by the conversion of the normal

protease-sensitive host prion protein (PrPsen)

to a disease-associated protease-resistant form

(PrPres). Although prion disease damages the

central nervous system (CNS), infectivity and

PrPres can be detected within peripheral tissues,

including lymphoid organs in humans, sheep,

and deer (1, 2), as well as skeletal muscle (3),

kidney, and pancreas (4) of some transgenic

rodent models. Despite the toxic effect on the

CNS, few if any histopathological changes have

been observed at peripheral sites.

Transmission of TSE disease to humans has

resulted from cannibalism, contaminated surgical

instrumentation, and tainted growth hormone

(5–7). A human disease termed variant

Creutzfeldt-Jakob disease (vCJD) has occurred

more recently, apparently through the ingestion

of bovine spongiform encephalopathy (BSE)–

infected cattle products (8). Recent evidence

suggests that transmission of vCJD between

humans may occur through blood transfusion

(9, 10), and this conclusion is supported by experimental

transmission of BSE between sheep

via blood transfusion (11). TSE infectivity has

been demonstrated in blood by intracerebralinoculation

in mouse, mink, hamster, and goat

models (7, 12–20). However, infectivity in such

cases is low, e102 50% infectious doses (ID50 )

per ml of blood compared to 106 to 1010 ID50/g

in the brain.

Normal prion protein, PrPsen, is expressed

primarily as a membrane-bound, glycophosphatydylinositol

(GPI)–anchored protein. The

role of cellular PrP membrane anchoring in

prion disease has been studied in transgenic

mice expressing GPI-negative anchorless PrP,

which is secreted from cells (21). Intracerebral

inoculation of these GPI-negative anchorless

PrP transgenic (tg) mice with murine scrapie

results in scrapie replication and deposition of

PrPres within the brain. Although wild-type

(WT) mice infected with scrapie usually develop

a nonamyloid form of PrPres, in these tg

mice the PrPres is primarily in the form of

amyloid plaques (21). At the same time, these

mice do not manifest the clinical and pathologic

alterations normally associated with prion disease,

thus demonstrating a separation between

PrPres amyloid accumulation and clinical CNS

disease (21). In the brain of these infected tg

mice, PrPres was located primarily within and

around endothelial cells (21) (Fig. 1A), leading

to the hypothesis that anchorless PrPres may be

secreted in the blood. Here we examined this


To determine whether PrPres and/or scrapie

infectivity was present in blood, four infected

tg mice were bled between 450 and 512 days

postinfection (dpi) with the RML strain of

scrapie. Inoculation of a 1:500 dilution of blood

from all four mice induced scrapie in WT

(C57BL/6) recipients in Č145 days. In addition,

blood of two mice analyzed by serial dilution

titration gave titers of Q1.6 107 and

Q1.6 105 ID50/ml blood (Table 1).

1Viral-Immunobiology Laboratory, Departments of Molecular

and Integrative Neurosciences and Infectology, Scripps

Research Institute, La Jolla, CA 92037, USA. 2Department

of Medicine, University of California, San Diego, La Jolla,

CA 92093, USA. 3Laboratory of Persistent Viral Diseases,

Rocky Mountain Laboratories, National Institute of Allergy

and Infectious Diseases, Hamilton, MT 59840, USA. 4Departments

of Neurosciences and Pathology, University of

California, San Diego, CA 92093, USA.

*To whom correspondence should be addressed. E-mail: (M.B.A.O.),

(B.C.), (K.U.K.)



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