Overexpression of mouse prion protein in transgenic mice causes a non-transmissible spongiform encephalopathy

Abstract

Transgenic mice over-expressing human PRNP or murine Prnp transgenes on a mouse prion protein knockout background have made key contributions to the understanding of human prion diseases and have provided the basis for many of the fundamental advances in prion biology, including the first report of synthetic mammalian prions. In this regard, the prion paradigm is increasingly guiding the exploration of seeded protein misfolding in the pathogenesis of other neurodegenerative diseases. Here we report that a well-established and widely used line of such mice (Tg20 or tga20), which overexpress wild-type mouse prion protein, exhibit spontaneous aggregation and accumulation of misfolded prion protein in a strongly age-dependent manner, which is accompanied by focal spongiosis and occasional neuronal loss. In some cases a clinical syndrome developed with phenotypic features that closely resemble those seen in prion disease. However, passage of brain homogenate from affected, aged mice failed to transmit this syndrome when inoculated intracerebrally into further recipient animals. We conclude that overexpression of the wild-type mouse prion protein can cause an age-dependent protein misfolding disorder or proteinopathy that is not associated with the production of an infectious agent but can produce a phenotype closely similar to authentic prion disease.

Figure 1

Distribution of spontaneous abnormal PrP and spongiform change in the brain of aged Tg20 mice challenged with D-PBS or buffer: The left hand panels show the typical histology which is the predominant feature of each group. (A and B) PrP immunohistochemistry using anti-PrP monoclonal antibody ICSM35 revealed abnormal PrP deposition including PrP-positive plaques. (C and D) Haematoxylin and eosin (H&E) stained sections showing spongiform neurodegeneration when present. Scale bar: 150 µm (A), 75 µm (B), and 300 µm (C and D). The right hand panels show schematic representations of mouse brain and indicate the spatial distribution of the pathology typical for each group. Abnormal PrP deposition is indicated in red and spongiform degeneration in blue.

Figure 2

The occurrence of spontaneous neuropathology in ageing Tg20 mice challenged with D-PBS or buffer: The x-axis represents the latency in days from inoculation to death with each symbol representing an individual animal (see Table 1). Triangles represent mice with cerebellar atrophy and circles indicate no atrophy. Blue symbols represent pattern (A), yellow symbols pattern (B), green symbols pattern (C) and (D) with open circles representing unaffected animals with no signs of abnormal pathology (see Fig. 1).

Figure 3

Age dependence of spontaneous neuropathology in Tg20 mice challenged with D-PBS or buffer. The proportion of Tg20 mice affected by neuropathological changes of all types (with patterns A, B and C) are shown as a percentage of the total number of mice examined in each of the age cohorts indicated on the x-axis. The numbers of mice affected were; < 500 days 0/3, 501–600 days 1/10, 601–700 days 7/18, 701–800 days 12/17 and > 801 days 5/6.