Abnormal prion protein is associated with changes of plasma membranes and endocytosis in bovine spongiform encephalopathy (BSE)‐affected cattle brains

Aims: Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative diseases of man and animals characterized by vacuolation and gliosis of neuropil and the accumulation of abnormal isoforms of a host protein known as prion protein (PrP). It is widely assumed that the abnormal isoforms of PrP (PrP d , disease‐specific form of PrP) are the proximate cause of neurodegeneration. Methods: To determine the nature of subcellular changes and their association with PrP d we perfusion‐fixed brains of eight bovine spongiform encephalopathy (BSE)‐affected cows and three control cattle for immunogold electron microscopy at two different neuroanatomical sites. Results: All affected cattle presented plasma membrane alterations of dendrites and astrocytes that were labelled for PrP d . PrP d on membranes of dendrites and occasionally of neuronal perikarya was associated with abnormal endocytotic events, including bizarre coated pits and invagination of the plasma membrane. BSE‐affected cattle also presented excess and abnormal multivesicular bodies, sometimes associated to the plasma membrane perturbations. In contrast, two TSE‐specific lesions, vacuolation and rare tubulovesicular bodies, were not labelled for PrP d as were a number of other nonspecific lesions, such as autophagy and dystrophic neurites. At least two different morphological pathways to vacuoles were recognized. Conclusions: When compared with other TSEs, these changes are common to those of sheep and rodent scrapie and shows that there are consistent membrane toxicity properties of PrP d . This toxicity involves an aberration of endocytosis. However, it is by no means clear that the lesions are of sufficient severity to result in clinical deficits.