Retinal Function and Morphology Are Altered in Cattle Infected with the Prion Disease Transmissible Mink Encephalopathy

Abstract

Abstract. Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy (''mad cow disease'') to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Mü ller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of new strategies for the diagnosis of TSEs.

Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

“…Our previous work has also demonstrated that changes in retinal function are detectable months prior to other signs of disease in cattle infected with transmissible mink encephalopathy [24]. Similarly, results presented here demonstrate that changes in retinal function as demonstrated by electroretinogram, specifically prolongation of the b-wave implicit time, are detectable at least 5 months prior to when cattle developed unequivocal signs of disease and were euthanized.…”

“…We used immunohistochemistry to assess any potential differences in these cell types in retinas from BSE-inoculated animals. Immunoreactivity for the alpha subunit of protein kinase-C (PKC-alpha) was used to examine the morphology of rod bipolar cells [24]. While we observed some subtle differences between samples, such as what appeared to be an increase of PKC-alpha immunoreactive processes in the retinas of animals inoculated with classical BSE, these differences were not sufficient for blinded investigators to sort inoculated samples from control samples (data not shown).…”

“…At this time the b-wave implicit time for-20 dB was approximately 58 milliseconds, and 29 milliseconds at 0dB, demonstrating virtually no change in the b-wave implicit time for these animals over three years time. Further, we compared the baseline results to previously published ERG values from Holstein steers at approximately 2 years of age [24]. In the non-inoculated animals in that study (at 2 years of age), the average b-wave implicit time for-20 dB was 62 milliseconds, and 29 milliseconds for 0dB.…”

“…The retina is the most accessible part of the CNS and is amenable to non-invasive assessment of morphology and function. We have previously demonstrated that functional changes develop in the retina of cattle inoculated with transmissible mink encephalopathy, a TSE with microscopic features similar to those of BSE [28], months prior to other clinical signs of disease [24]. Here we describe changes in retinal morphology and function over time in animals inoculated with two different strains of BSE; classical foodborne BSE, which transmits to humans as vCJD [6,29,30], and atypical high-type BSE (BSE-H) diagnosed in the US in 2004 [31].…”

Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism

“…As the retina has proven to offer diagnostic promise in TSEs [32], [33], two non-invasive tools were utilized to assess retinal changes during the incubation period. Retinal function and thickness were assessed through electroretinography and optical coherence tomography (OCT), respectively.…”