THE 139H SCRAPIE AGENT PRODUCES HYPOTHALAMIC NEUROTOXICITY AND PANCREATIC-ISLET HISTOPATHOLOGY - ELECTRON-MICROSCOPIC STUDIES

Neuronal degeneration, along with astrocytosis, spongiform vacuolation , and amyloid (PrPSc) formation, have long been regarded as neuropatho logical hallmarks of transmissible spongiform encephalopathies (TSEs). In animals, these diseases include; scrapie, transmissible mink encep halopathy, chronic wasting disease, bovine and feline spongiform encep halopathies, and in humans; kuru, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS). The abnormal amyloid pr otein, (PrPSc) is toxic to neurons. Our previous studies showed that h amsters treated with 139H scrapie strain developed obesity, and genera lized endocrinopathy, including lesions in hypothalamus, pituitary and pancreas. Histochemical and immunocytochemical studies revealed exten sive pathological changes in the islets of Langerhans in 139H-infected hamsters, but not in hamsters infected with 263K scrapie strain. Usin g routine electron microscopy (EM) we have observed more details of le sions in the beta cells of islets of Langerhans in these animals. Cyto plasmic vacuolation occurred, cytoplasmic organelles were found damage d and disrupted, and membranes were occasionally ruptured. The width o f endoplasmic reticulum (ER) lumina were 50-150 nm in controls, wherea s in 139H-infected hamsters, they were occasionally increased up to 40 00 nm in diameter. Most beta cells showed degranulation. These EM obse rvations suggest that the cellular death seen in the islets of Langerh ans in 139H-infected hamsters is due to necrosis, not apoptosis. Since there were no amyloid deposits found in the islet of Langerhans at th e EM level, and there were extremely low scrapie infectivity levels an d PrP S' levels in pancreas, it is suggested that the changes noted in pancreas were not a direct toxic effect of PrPSc. Instead, our study suggests that scrapie prion protein PrP S', acting as a neurotoxicant, alters the hypothalamic neuroendocrine regulation of the pancreas. (C ) 1997 Inter Press, Inc.