title: Time-course studies of 14-3-3 protein isoforms in cerebrospinal fluid and brain of primates after oral or intracerebral infection with bovine spongiform encephalopathy agent.
abstract: Experimental transmission of bovine spongiform encephalopathy (BSE) to cynomolgus monkeys (Macaca fascicularis) is an animal model for variant Creutzfeldt-Jakob disease (vCJD). The presence of 14-3-3 proteins in cerebrospinal fluid (CSF) samples indicates neuronal destruction and is therefore used as a clinical biomarker. However, time-course studies using 14-3-3 proteins have not been performed until now in simian vCJD. The main goals of this study were to determine isoform patterns, to examine kinetics and to correlate the clinical course with the occurrence of this biomarker in simian vCJD. In monkeys dosed intracerebrally with BSE, the earliest clinical sign of illness was a drop in body weight that was detected months before the onset of mild neurological signs. Macaques dosed orally or intracerebrally with BSE developed neurological signs 4.3 (3.7-4.6) and 4.8 (2.9-6.0) years post-infection, respectively. 14-3-3beta- and -gamma-positive CSF samples were found around the time of onset of mild neurological signs, but not earlier. In contrast, 14-3-3epsilon and -eta isoforms were not detectable. 14-3-3 levels increased with time and were positively correlated with the degree of neurological symptoms. Post-mortem examination of brain samples revealed a positive correlation between PrP res and 14-3-3epsilon levels. Interestingly, florid plaques characteristic of human vCJD could not be detected in diseased monkeys. It was concluded that analysis of 14-3-3 proteins in CSF is a reliable tool to characterize the time course of brain degeneration in simian vCJD. However, there are differences in the clinical course between orally and intracerebrally infected animals that may influence the detection of other biomarkers.
authors.affiliation: Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Yutzy
authors.affiliation: Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Holznagel
authors.affiliation: Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Cheick
authors.initials: C
authors.lastname: Coulibaly
authors.affiliation: Department of Virology and Immunology, German Primate Centre, Göttingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stuke
authors.affiliation: Department of Virology and Immunology, German Primate Centre, Göttingen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hahmann
authors.affiliation: Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Deslys
authors.affiliation: Department of Virology and Immunology, German Primate Centre, Göttingen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hunsmann
authors.affiliation: Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Löwer
mesh_terms: D048948:14-3-3 Proteins / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D018450:Disease Progression; D016643:Encephalopathy, Bovine Spongiform / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020234:Gait Ataxia / Q000473:pathology; D008252:Macaca fascicularis; D018620:PrPSc Proteins / Q000302:isolation & purification; D012925:Social Conformity; D013997:Time Factors; D015431:Weight Loss
chemical_list: D048948:14-3-3 Proteins; D018620:PrPSc Proteins