Prion diseases and Alzheimer disease (AD) share a variety of clinical and neuropathologic features (e.g. progressive dementia, accumulation of abnormally folded proteins in diseased tissue, and pronounced neuronal loss) as well as pathogenic mechanisms like generation of oxidative stress molecules and complement activation. Recently, it was suggested that neuronal death in AD may have its origin in the endoplasmic reticulum (ER). Cellular stress conditions can interfere with protein folding and subsequently cause accumulation of unfolded or misfolded proteins in the ER lumen. The ER responds to this by the activation of adaptive pathways, which are termed unfolded protein response (UPR). The UPR transducer PERK, which launches the most immediate response to ER stress (i.e. the transient attenuation of mRNA translation), and the downstream effector of PERK, eIF2alpha, were shown to be activated in AD. We demonstrate that neither in sporadic nor in infectiously acquired or inherited human prion diseases can the activated forms of PERK and eIF2alpha be detected, except when concomitant neurofibrillary pathology is present; whereas the distribution of phosphorylated PERK correlates with abnormally phosphorylated tau in AD. In brains of scrapie-affected mice and mice infected with sporadic or variant Creutzfeldt-Jakob disease, activated PERK is only very faintly expressed. The lack of prominent activation of the PERK-eIF2alpha pathway in prion diseases suggests that, in contrast to AD, ER stress does not play a crucial role in neuronal death in prion disorders.

The presence of the cellular prion protein (PrPC) on the cell surface is critical for the neurotoxicity of prions. Although a number of biological activities have been attributed to PrPC, a definitive demonstration of its physiological function remains elusive. In this review, we will discuss some of the proposed functions of PrPC, focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane, and neuroprotection. We will also discuss recent evidence supporting the idea that PrPC may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrPC and its role in neurodegenerative diseases beyond those caused by prions.

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP Sc) binds to the cellular form (PrP C), generating additional molecules of PrP Sc. While several regions of the PrP C molecule have been suggested to play a role in PrP Sc formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23–31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrP Sc. These results, in combination with biochemical data, demonstrate that residues 23–31 represent a critical site on PrP C that binds to PrP Sc and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrP C.

1 P2Y receptors inhibiting adenylyl cyclase have been found in blood platelets, glioma cells, and endothelial cells. In platelets and glioma cells, these receptors were identi®ed as P2Y 12 . Here, we have used PC12 cells to search for adenylyl cyclase inhibiting P2Y receptors in a neuronal cellular environment. 2 ADP and ATP (0.1 ± 100 mM) left basal cyclic AMP accumulation unaltered, but reduced cyclic AMP synthesis stimulated by activation of endogenous A 2A or recombinant b 2 receptors. Forskolindependent cyclic AMP production was reduced by 41 mM and enhanced by 10 ± 100 mM ADP; this latter e ect was turned into an inhibition when A 2A receptors were blocked. 3 The nucleotide inhibition of cyclic AMP synthesis was not altered when P2X receptors were blocked, but abolished by pertussis toxin. 4 The rank order of agonist potencies for the reduction of cyclic AMP was (IC 50 values): 2-methylthio-ADP (0.12 nM)=2-methylthio-ATP (0.13 nM)4ADPbS (71 nM)4ATP (164 nM)=ADP (244 nM). The inhibition by ADP was not antagonized by suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid, or adenosine-3'-phosphate-5'-phosphate, but attenuated by reactive blue 2, ATPaS, and 2-methylthio-AMP. 5 RT ± PCR demonstrated the expression of P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 12 , but not P2Y 1 , receptors in PC12 cells. In Northern blots, only P2Y 2 and P2Y 12 were detectable. Di erentiation with NGF did not alter these hybridization signals and left the nucleotide inhibition of adenylyl cyclase unchanged.

Several lines of evidence suggest that the normal form of the prion protein, PrPC, exerts a neuroprotective activity against cellular stress or toxicity. One of the clearest examples of such activity is the ability of wild-type PrPC to suppress the spontaneous neurodegenerative phenotype of transgenic mice expressing a deleted form of PrP (Δ32–134, called F35). To define domains of PrP involved in its neuroprotective activity, we have analyzed the ability of several deletion mutants of PrP (Δ23–31, Δ23–111, and Δ23–134) to rescue the phenotype of Tg(F35) mice. Surprisingly, all of these mutants displayed greatly diminished rescue activity, although Δ23–31 PrP partially suppressed neuronal loss when expressed at very high levels. Our results pinpoint the N-terminal, polybasic domain as a critical determinant of PrPC neuroprotective activity, and suggest that identification of molecules interacting with this region will provide important clues regarding the normal function of the protein. Small molecule ligands targeting this region may also represent useful therapeutic agents for treatment of prion diseases.