Neuropathological changes correlate temporally but not spatially with selected neuromodulatory responses in natural scrapie.
OBJECTIVE
Neuropathological changes classically associated with sheep scrapie do not always correlate with clinical disease. We aimed to determine if selected neuromodulatory responses were altered during the course of the infection as it has been described in Creutzfeldt-Jakob disease and experimental bovine spongiform encephalopathy.


METHODS
Hemi-brains from healthy sheep and natural scrapie cases at two stages of infection were examined for biochemical alterations related to the expression of type I metabotropic glutamatergic receptors (mGluR(1) ) and type I adenosine receptors I (A(1) R), and of selected downstream intermediate signalling targets. Immunohistochemistry for different scrapie-related neuropathological changes was performed in the contralateral hemi-brains.


RESULTS
PrP(d) deposition, spongiform change, astrocytosis and parvalbumin expression were significantly altered in brains from clinically affected sheep compared with preclinical cases and negative controls; the latter also showed significantly higher immunoreactivity for synaptophysin than clinical cases. Between clinically affected and healthy sheep, no differences were found in the protein levels of mGluR(1) , while phospholipase Cβ1 expression in terminally ill sheep was increased in some brain areas but decreased in others. Adenyl cyclase 1 and A(1) R levels were significantly lower in various brain areas of affected sheep. No abnormal biochemical expression levels of these markers were found in preclinically infected sheep.


CONCLUSIONS
These findings point towards an involvement of mGluR(1) and A(1) R downstream pathways in natural scrapie. While classical prion disease lesions and neuromodulatory responses converge in some affected regions, they do not do so in others suggesting that there are independent regulatory factors for distinct degenerative and neuroprotective responses.
Veterinary Laboratories Agency Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, UK. s.siso@vla.defra.gsi.gov.uk
S
S
Sisó
L
L
González
R
R
Blanco
F
F
Chianini
H W
HW
Reid
M
M
Jeffrey
I
I
Ferrer
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis*; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis*; D012608:Scrapie / Q000378:metabolism* / Q000473:pathology*; D012756:Sheep
D043682:Receptor, Adenosine A1; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1