Squirrel monkeys (Saimiri sciureus) infected with the agent of bovine spongiform encephalopathy develop tau pathology

Abstract

Squirrel monkeys (Saimiri sciureus) were infected experimentally with the agent of classical bovine spongiform encephalopathy (BSE). Two to four years later, six of the monkeys developed alterations in interactive behaviour and cognition and other neurological signs typical of transmissible spongiform encephalopathy (TSE). At necropsy examination, the brains from all of the monkeys showed pathological changes similar to those described in variant Creutzfeldt-Jakob disease (vCJD) of man, except that the squirrel monkey brains contained no PrP-amyloid plaques typical of that disease. Constant neuropathological features included spongiform degeneration, gliosis, deposition of abnormal prion protein (PrP(TSE)) and many deposits of abnormally phosphorylated tau protein (p-Tau) in several areas of the cerebrum and cerebellum. Western blots showed large amounts of proteinase K-resistant prion protein in the central nervous system. The striking absence of PrP plaques (prominent in brains of cynomolgus macaques [Macaca fascicularis] with experimentally-induced BSE and vCJD and in human patients with vCJD) reinforces the conclusion that the host plays a major role in determining the neuropathology of TSEs. Results of this study suggest that p-Tau, found in the brains of all BSE-infected monkeys, might play a role in the pathogenesis of TSEs. Whether p-Tau contributes to development of disease or appears as a secondary change late in the course of illness remains to be determined.

Figure 1

Lesion profile patterns of spongiform degeneration (a), PrP deposition (b), and gliosis (c) observed in brains of six squirrel monkeys inoculated with BSE agent (red). Data obtained with sections from the brain of an uninfected a squirrel monkey used as control are in black. The profiles were produced from mean scores (with standard deviations) for nine brain areas: F frontal cortex, T temporal cortex, O occipital cortex, GN geniculate nucleus, HI hippocampus, Crb cerebellum, BS brain stem, Wcx white mater cerebral cortex, Wcrb white matter cerebellum.

Figure 2

Severe spongiform degeneration and PrP deposition in the frontal cortex of a squirrel monkey inoculated with the BSE agent. Fine punctate, perivacuolar, pericellular and linear PrP deposits (arrows) are shown in panel b. Panel a hematoxylin-eosin, panel b immunostained with anti-PrP antibody 6H4.

Figure 3

Comparative Western blot (WB) analysis of prion protein in cBSE inoculum; human vCJD (World Health Organization Candidate Biological Reference CJD, material prepared and distributed by J. Cooper, K. Sadhani and P. Minor, UK National Institute for Biological Standards and Control (NIBSC); and brain extracts from squirrel monkeys with TSE disease confirmed neuropathologically (721, 722, 735, 737, 738 and 739). Brain from squirrel monkey 659 with no neurological illness or spongiform encephalopathy served as normal control. Non-PK-treated (−) and PK-treated samples (+). Molecular mass is indicated on the left of the panel. Filters were probed with anti-prion protein antibody 6D11.

Figure 4

Abundant p-Tau-immunoreactive deposits in the cerebral cortex of a squirrel monkey 735 inoculated with BSE agent (a). PrP accumulation (b) and p-Tau profiles (c) in the cerebellum of squirrel monkey 739 inoculated with the BSE agent. p-Tau immunopositivity is seen in the molecular and granule cell layers of the cerebellum (arrows). p-Tau immunostaining using anti-phosphorylated tau protein AT8 shown in panels a and c, PrP immunostaining using anti-prion protein antibody 6H4 shown in panel b.