Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein.

Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an unprecedented promiscuity for diverse prion isolates, arguing that bank vole PrP (BVPrP) may be inherently prone to adopting misfolded conformations. Therefore, we constructed transgenic (Tg) mice expressing WT BVPrP. Tg(BVPrP) mice developed spontaneous CNS dysfunction between 108 and 340 d of age and recapitulated the hallmarks of prion disease, including spongiform degeneration, pronounced astrogliosis, and deposition of alternatively folded PrP in the brain. Brain homogenates of ill Tg(BVPrP) mice transmitted disease to Tg(BVPrP) mice in ∼35 d, to Tg mice overexpressing mouse PrP in under 100 d, and to WT mice in ∼185 d. Our studies demonstrate experimentally that WT PrP can spontaneously form infectious prions in vivo. Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD.

Purified and synthetic Alzheimer's amyloid beta (Aß) prions.

The aggregation and deposition of amyloid-ß (Aß) peptides are believed to be central events in the pathogenesis of Alzheimer's disease (AD). Inoculation of brain homogenates containing Aß aggregates into susceptible transgenic mice accelerated Aß deposition, suggesting that Aß aggregates are capable of self-propagation and hence might be prions. Recently, we demonstrated that Aß deposition can be monitored in live mice using bioluminescence imaging (BLI). Here, we use BLI to probe the ability of Aß aggregates to self-propagate following inoculation into bigenic mice. We report compelling evidence that Aß aggregates are prions by demonstrating widespread cerebral ß-amyloidosis induced by inoculation of either purified Aß aggregates derived from brain or aggregates composed of synthetic Aß. Although synthetic Aß aggregates were sufficient to induce Aß deposition in vivo, they exhibited lower specific biological activity compared with brain-derived Aß aggregates. Our results create an experimental paradigm that should lead to identification of self-propagating Aß conformations, which could represent novel targets for interrupting the spread of Aß deposition in AD patients.

Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer's disease.

Transgenic (Tg) mouse models of Alzheimer's disease have served as valuable tools for investigating pathogenic mechanisms related to Aß accumulation. However, assessing disease status in these animals has required time-consuming behavioral assessments or postmortem neuropathological analysis. Here, we report a method for tracking the progression of Aß accumulation in vivo using bioluminescence imaging (BLI) on two lines of Tg mice, which express luciferase (luc) under control of the Gfap promoter as well as mutant human amyloid precursor protein. Bigenic mice exhibited an age-dependent increase in BLI signals that correlated with the deposition of Aß in the brain. Bioluminescence signals began to increase in 7-mo-old Tg(CRND8:Gfap-luc) mice and 14-mo-old Tg(APP23:Gfap-luc) mice. When Tg(APP23:Gfap-luc) mice were inoculated with brain homogenates from aged Tg(APP23) mice, BLI detected the accelerated disease onset and induced Aß deposition at 11 mo of age. Because of its rapid, noninvasive, and quantitative format, BLI permits the objective repeated analysis of individual mice at multiple time points, which is likely to facilitate the testing of Aß-directed therapeutics.