Prion Protein PrPc Research Articles

Differential Toxicity of Antibodies to the Prion Protein.

Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.

Cellular prion protein regulates invasion and migration of breast cancer cells through MMP-9 activity

Function of cellular prion protein (PrPc) in cancer progression has not been elucidated yet. Ectopic expression of PrPc increases the invasion and migration of breast cancer cell line, MCF-7 cells. Overexpressed PrPc increases matrix metalloprotease-9 (MMP-9) expression by enhancing association of NF-κB in promoter of MMP-9 gene and ERK signaling in MCF-7 cells. Whereas, silencing of PrPc by siRNA suppresses ERK activation and MMP-9 expression resulting the down-regulation of MD-MB231 cell migration and invasion. Overall, these results suggest that PrPc contribute the breast cancer invasion and migration via MMP-9.

Brain biopsy in the diagnosis of Creutzfeldt-Jakob disease with a history of prodromal psychiatric symptoms and catatonic behavior

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies. Transition of physiological, soluble, neuroprotective prion protein PrPc into its insoluble, misfolded isoform PrPSc remains the central pathogenic event in this disorder. Their progressive accumulation within the brain tissue results in spongiform degeneration and plethora of clinical symptoms. Typically, CJD manifests as progressive dementia with myoclonus, visual or cerebellar dysfunction, pyramidal/extrapyramidal signs or akinetic mutism. However, growing number of studies indicate that CJD may present with prodromal psychiatric manifestations including anhedonia, anxiety, irritability, depression, insomnia, psychosis and catatonic behaviour. We present case of biopsy proven CJD with a history of prodromal psychiatric symptoms and catatonic behaviour.

Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition.

Although cellular prion protein (PrPc) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrPc in post-ischemic brain remodeling, we herein exposed PrPc wild type (WT), PrPc knockout (PrP−/−) and PrPc overexpressing (PrP+/+) mice to focal cerebral ischemia followed by up to 28 days reperfusion. Improved neurological recovery and sustained neuroprotection lasting over the observation period of 4 weeks were observed in ischemic PrP+/+ mice compared with WT mice. This observation was associated with increased neurogenesis and angiogenesis, whereas increased neurological deficits and brain injury were noted in ischemic PrP−/− mice. Proteasome activity and oxidative stress were increased in ischemic brain tissue of PrP−/− mice. Pharmacological proteasome inhibition reversed the exacerbation of brain injury induced by PrP−/−, indicating that proteasome inhibition mediates the neuroprotective effects of PrPc. Notably, reduced proteasome activity and oxidative stress in ischemic brain tissue of PrP+/+ mice were associated with an increased abundance of hypoxia-inducible factor 1α and PACAP-38, which are known stimulants of neural progenitor cell (NPC) migration and trafficking. To elucidate effects of PrPc on intracerebral NPC homing, we intravenously infused GFP+ NPCs in ischemic WT, PrP−/− and PrP+/+ mice, showing that brain accumulation of GFP+ NPCs was greatly reduced in PrP−/− mice, but increased in PrP+/+ animals. Our results suggest that PrPc induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity.

Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo

Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrPc) to the aberrant conformationally altered isoform; PrPSc. This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases.

Transgenic Rabbits Expressing Ovine PrP Are Susceptible to Scrapie.

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting a wide range of mammalian species. They are caused by prions, a proteinaceous pathogen essentially composed of PrPSc, an abnormal isoform of the host encoded cellular prion protein PrPC. Constrained steric interactions between PrPSc and PrPC are thought to provide prions with species specificity, and to control cross-species transmission into other host populations, including humans. Transgenetic expression of foreign PrP genes has been successfully and widely used to overcome the recognized resistance of mouse to foreign TSE sources. Rabbit is one of the species that exhibit a pronounced resistance to TSEs. Most attempts to infect experimentally rabbit have failed, except after inoculation with cell-free generated rabbit prions. To gain insights on the molecular determinants of the relative resistance of rabbits to prions, we generated transgenic rabbits expressing the susceptible V136R154Q171 allele of the ovine PRNP gene on a rabbit wild type PRNP New Zealand background and assessed their experimental susceptibility to scrapie prions. All transgenic animals developed a typical TSE 6–8 months after intracerebral inoculation, whereas wild type rabbits remained healthy more than 700 days after inoculation. Despite the endogenous presence of rabbit PrPC, only ovine PrPSc was detectable in the brains of diseased animals. Collectively these data indicate that the low susceptibility of rabbits to prion infection is not enciphered within their non-PrP genetic background.

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation.

In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases.

The cellular prion protein PrPc is a partner of the Wnt pathway in intestinal epithelial cells.

We reported previously that the cellular prion protein (PrP(c)) is a component of desmosomes and contributes to the intestinal barrier function. We demonstrated also the presence of PrP(c) in the nucleus of proliferating intestinal epithelial cells. Here we sought to decipher the function of this nuclear pool. In human intestinal cancer cells Caco-2/TC7 and SW480 and normal crypt-like HIEC-6 cells, PrP(c) interacts, in cytoplasm and nucleus, with γ-catenin, one of its desmosomal partners, and with β-catenin and TCF7L2, effectors of the canonical Wnt pathway. PrP(c) up-regulates the transcriptional activity of the β-catenin/TCF7L2 complex, whereas γ-catenin down-regulates it. Silencing of PrP(c) results in the modulation of several Wnt target gene expressions in human cells, with different effects depending on their Wnt signaling status, and in mouse intestinal crypt cells in vivo. PrP(c) also interacts with the Hippo pathway effector YAP, suggesting that it may contribute to the regulation of gene transcription beyond the β-catenin/TCF7L2 complex. Finally, we demonstrate that PrP(c) is required for proper formation of intestinal organoids, indicating that it contributes to proliferation and survival of intestinal progenitors. In conclusion, PrP(c) must be considered as a new modulator of the Wnt signaling pathway in proliferating intestinal epithelial cells.

Cellular prion protein directly interacts with and enhances lactate dehydrogenase expression under hypoxic conditions

Although a physiological function of the cellular prion protein (PrPc) is still not fully clarified, a PrPc-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion protein knockout mice (Prnp0/0) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrPc. Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp0/0 knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line.While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp0/0 primary cortical neurons with concurrent less hypoxia-induced damage in the former group. Likewise, cerebral ischemia significantly increases LDH levels in WT vs. Prnp0/0 mice with accompanying smaller lesions in the WT group. HEK293 cells overexpressing PrPc show significantly higher LDH expression/activity following 90-min of hypoxia as compared to control cells. Moreover, a cytoplasmic co-localization of LDH and PrPc was recorded under both normoxic and hypoxic conditions. Interestingly, an expression of monocarboxylate transporter 1, responsible for cellular lactate uptake, increases with PrPc-overexpression under normoxic conditions. Our data suggest LDH as a direct PrPc interactor with possible physiological relevance under low oxygen conditions.

Zinc significantly changes the aggregation pathway and the conformation of aggregates of human prion protein

Prion diseases are caused by the conformational change of cellular prion protein PrPC into pathological prion protein PrPSc. Here we study the effect of zinc on the aggregation and conformational change of human prion protein (PrP). As revealed by thioflavin T binding assays, Sarkosyl-soluble SDS-PAGE, and transmission electron microscopy, aggregation of wild-type PrP in the absence of Zn2+ undergoes four steps: amorphous aggregates, profibrils, mature fibrils, and fragmented fibrils. When the molar ratio of Zn2+ to PrP was 9:1, however, aggregation of wild-type PrP undergoes another pathway in which wild-type PrP forms oligomers quickly and then forms short-rod aggregates. Unlike wild-type PrP, the octarepeats deletion mutant PrPΔocta forms typical mature fibrils either with or without zinc. As evidenced by isothermal titration calorimetry, Fourier transform infrared spectroscopy, and proteinase K digestion assays, Zn2+ strongly binds to wild-type PrP monomers with the first binding constant exceeding 107M−1 under denaturing conditions, and changes the conformation of wild-type PrP aggregates remarkably, but weakly binds to PrPΔocta with binding affinity around 104M−1 and has no obvious effects on the conformation of PrPΔocta aggregates. Our data demonstrate that zinc significantly changes the aggregation pathway and the conformation of wild-type PrP aggregates mainly via interaction with its octarepeat region. Our findings could explain how zinc modifies pathological PrP conformation associated with prion diseases.

Glutamate receptors function as scaffolds for the regulation of β-amyloid and cellular prion protein signaling complexes.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects 36 million people worldwide, but currently has no effective treatment options. One of the original hallmarks of AD are plaques comprised of beta amyloid (Aβ) and neurofibrillary tangles comprised of phosphorylated Tau protein. However, it is soluble oligomeric Aβ which is more closely correlated with cognitive decline and is therefore considered to be the neurotoxic species. Oligomeric Aβ has recently been shown to form complexes with the glycosylphosphatidylinositol (GPI)-anchored membrane protein, cellular prion protein (PrPc), and these complexes are believed to play an important role in the progression of AD pathogenesis. Glutamate, the major excitatory neurotransmitter is responsible for mediating learning and memory under normal physiological conditions. However, the dysregulation of glutamatergic signaling has also been implicated in a number of neurodegenerative diseases including AD. Glutamate acts via both ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR), each of which have been implicated in AD. There is now growing evidence to suggest that mGluR5 may contribute the AD pathogenesis by acting as scaffolds for the PrPc/Aβ oligomer complex, enabling the propagation of neurotoxic signaling in AD. In addition, PrPc and Aβ oligomer signaling via NMDARs may also contribute to AD pathology. The current review overviews our current understanding of the role of PrPc and Aβ oligomers in regulating glutamate receptor signaling, as well as highlights the importance of understanding these signaling complexes to develop more effective therapeutic strategies to treat AD.

Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways

Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection.

Prion pathogenesis in the absence of NLRP3/ASC inflammasomes.

The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.

Promiscuous functions of the prion protein family.

From the discovery nearly 30 years ago of the cellular prion protein PrPC, the founder of the prion protein family, there has been a constant quest to dissect its biological function and that of its two homologs, Doppel and Shadoo. While clues were greatly anticipated from the generation of PrP null mice, alterations appeared quite imperceptible at first examination, beyond the clear-cut resistance to prion infection. Taking a closer look at these knockout mice, together with the generation of mice invalidated for Doppel and Shadoo has in the end yielded much information on the -sometimes overlapping- roles of these proteins. These in-depth investigations have also explored functions of the prion protein family beyond the central nervous system, which was obviously the first focus of interest since prion diseases are neurodegenerative disorders. This Frontiers Research topic on the promiscuous functions of the prion protein family incorporates contributions ranging from the field of developmental biology to that of structure-function, including aspects related to cell biology, signal transduction, and neuronal homeostasis.

Induction of cellular prion protein (PrPc) under hypoxia inhibits apoptosis caused by TRAIL treatment.

Hypoxia decreases cytotoxic responses to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. Cellular prion protein (PrPc) is regulated by HIF-1α in neurons. We hypothesized that PrPc is involved in hypoxia-mediated resistance to TRAIL-induced apoptosis. We found that hypoxia induced PrPc protein and inhibited TRAIL-induced apoptosis. Thus silencing of PrPc increased TRAIL-induced apoptosis under hypoxia. Overexpression of PrPc protein using an adenoviral vector inhibited TRAIL-induced apoptosis. In xenograft model in vivo, shPrPc transfected cells were more sensitive to TRAIL-induced apoptosis than in shMock transfected cells. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia.

Synthetic Scrapie Infectivity: Interaction between Recombinant PrP and Scrapie Brain-Derived RNA

The key molecular event in human cerebral proteinopathies, which include Alzheimer's, Parkinson's and Huntington's diseases, is the structural conversion of a specific host protein into a β-sheet-rich conformer. With regards to this common mechanism, it appears difficult to explain the outstanding infectious properties attributed to PrPSc, the hallmark of another intriguing family of cerebral proteinopathies known as transmissible spongiform encephalopathies (TSE) or prion diseases. The infectious PrPSc or "prion" is thought to be composed solely of a misfolded form of the otherwise harmless cellular prion protein (PrPc). To gain insight into this unique situation, we used the 263K scrapie hamster model to search for a putative PrPSc-associated factor that contributes to the infectivity of PrPSc amyloid. In a rigorously controlled set of experiments that included several bioassays, we showed that originally innocuous recombinant prion protein (recPrP) equivalent to PrPc is capable of initiating prion disease in hamsters when it is converted to a prion-like conformation (β-sheet-rich) in the presence of RNA purified from scrapie-associated fibril (SAF) preparations. Analysis of the recPrP-RNA infectious mixture reveals the presence of 2 populations of small RNAs of approximately 27 and 55 nucleotides. These unprecedented findings are discussed in light of the distinct relationship that may exist between this RNA material and the 2 biological properties, infectivity and strain features, attributed to prion amyloid.

Prion Diseases and their Prpsc-Based Molecular Diagnostics

Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are fatal neurodegenerative disorders with characteristic sponge-like microscopic appearance in the infected brain. They are caused by a protein-only particle consisting of an abnormal isoform (PrPSc) of the normal ubiquitous cellular prion protein PrPc. Prion diseases affect both human and animals, and can cause interspecies Corbiere. In humans, there are six different phonotypes of prion diseases, including kuru disease, Creutzfeldt-Jakob disease (CJD), Gerstmann- Straussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia (FFI), variant Creutzfeldt-Jakob disease (vCJD) and variably protease sensitive prionopathy (VPSPr). There are five well-studied prion diseases in herbivorous animals and carnivorous animals, including scrapie, Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Transmissible Mink Encephalopathy (TME), and Feline Spongiform Encephalopathy (FSE). As the pathogen of the diseases, PrPSc accumulates in tissues and body fluids of the affected individuals, and serves as the most reliable marker for diagnosis of prion diseases. The bioassay, immunoblotting, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) tests have been used in prion disease diagnosis and surveillance, but they are not sufficient for the preclinical diagnosis. The newly improved in vitro PrPSc amplification methods, such as protein misfolding cyclic amplification (PMCA), amyloid seeding assay (ASA), and real-time quaking-induced conversion (RT-QUIC), showed greatly increased sensitivity. Recently, RT-QUIC and PMCA were applied to noninvasive tests targeting PrPSc in urine or nasal swab, making early diagnosis and surveillance of prion diseases become more practical.

D-Leucine Suppresses Prion Formation in Prion-Infected Culture Cells

Prion disease is an infectious and fatal disease. The pathogen consists of an abnormal form of the prion protein; designated PrP Sc . PrP Sc is insoluble, highly resistant to digestion by proteases and all disinfectants. In contrast, the cellular form of prion protein PrPC is easily soluble and digested by proteases. Direct interaction between PrP Sc and PrP C is believed to induce the propagation of prions; however, the molecular mechanisms underlying this step have not been clarified. Despite efforts to find molecules that can specifically interact with the prion protein conformer and thereby inhibit prion production through disruption of PrPSc and PrPC interaction, and thus may disturb prion production by inhibiting the above interaction, there is no efficient way to date and data regarding this issue are limited. Our findings provide novel insight into possible therapeutic approaches for treating prion disease.

Alzheimer's Aβ interacts with cellular prion protein inducing neuronal membrane damage and synaptotoxicity

A major feature of Alzheimer's disease is the accumulation of β-amyloid (Aβ) peptide in the brain. Recent studies have indicated that Aβ oligomers (Aβo) can interact with the cellular prion protein (PrPc). Therefore, this interaction might be driving some of Aβ toxic effects in the synaptic region. In the present study, we report that Aβo binds to PrPc in the neuronal membrane playing a role on toxic effects induced by Aβ. Phospholipase C-enzymatic cleavage of PrPc from the plasma membrane attenuated the association of Aβo to the neurons. Furthermore, an anti-PrP antibody (6D11) decreased the association of Aβo to hippocampal neurons with a concomitant reduction in Aβo and PrPc co-localization. Interestingly, this antibody blocked the increase in membrane conductance and intracellular calcium induced by Aβo. Thus, the data indicate that PrPc plays a role on the membrane perforations produced by Aβo, the increase in calcium ions and the release of synaptic vesicles that subsequently leads to synaptic failure. Future studies blocking Aβo interaction with PrPc could be important for the discovery of new therapeutic strategies for Alzheimer's disease.

CNS infections in 2014: guns, germs, and will

CNS infections in 2014: guns, germs, and will