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Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrPC selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron‐restricted PrPC expression led to copious brain accumulation of PrPSc. As expected, neuron‐restricted expression was associated with typical prion disease. However, mice with astrocyte‐restricted PrPC expression experienced a normal life span, did not develop clinical disease, and did not show astro‐ or microgliosis. Besides confirming that PrPSc is innocuous to PrPC‐deficient neurons, these results show that astrocyte‐born PrPSc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion‐infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction. [ABSTRACT FROM AUTHOR]

Protease-resistant prion protein (PrP) is diagnostic of prion disease, yet its detection is frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical familial prion disease. Brain PrP was undetectable by conventional Western blotting and barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern suggestive of noncanonical conformation. Therefore, we used a novel misfolded protein assay (MPA) that detects PrP aggregates independently of their protease resistance. The MPA revealed the presence of aggregated PrP in similar amounts as in typical sporadic Creutzfeldt-Jakob disease. These findings suggest that measurements of PrP aggregation with the MPA may be potentially more sensitive than protease-based methodologies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common neurodegenerative disorder, goes along with extracellular amyloid-β (Aβ) deposits. The cognitive decline observed during AD progression correlates with damaged spines, dendrites and synapses in hippocampus and cortex. Numerous studies have shown that Aβ oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions. The cellular prion protein (PrPC) was proposed to mediate this effect. We report that ablation or overexpression of PrPC had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrPC as a mediator of Aβ toxicity. See accompanying article: http://dx.doi.org/10.1002/emmm.2010000868. [ABSTRACT FROM AUTHOR]

Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrPC selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron‐restricted PrPC expression led to copious brain accumulation of PrPSc. As expected, neuron‐restricted expression was associated with typical prion disease. However, mice with astrocyte‐restricted PrPC expression experienced a normal life span, did not develop clinical disease, and did not show astro‐ or microgliosis. Besides confirming that PrPSc is innocuous to PrPC‐deficient neurons, these results show that astrocyte‐born PrPSc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion‐infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction. [ABSTRACT FROM AUTHOR]