Role Of Cellular Prion Protein Research Articles

The role of cellular prion protein in immune system

The role of cellular prion protein in immune system

The Role of Cellular Prion Protein in Glioma Tumorigenesis Could Be through the Autophagic Mechanisms: A Narrative Review.

The carcinogenesis of glial tumors appears complex because of the many genetic and epigenetic phenomena involved. Among these, cellular prion protein (PrPC) is considered a key factor in cell-death resistance and important aspect implicated in tumorigenesis. Autophagy also plays an important role in cell death in various pathological conditions. These two cellular phenomena are related and share the same activation by specific alterations in the cellular microenvironment. Furthermore, there is an interdependence between autophagy and prion activity in glioma tumorigenesis. Glioma is one of the most aggressive known cancers, and the fact that such poorly studied processes as autophagy and PrPC activity are so strongly involved in its carcinogenesis suggests that by better understanding their interaction, more can be understood about its origin and treatment. Few studies in the literature relate these two cellular phenomena, much less try to explain their combined activity and role in glioma carcinogenesis. In this study, we explored the recent findings on the molecular mechanism and regulation pathways of autophagy, examining the role of PrPC in autophagy processes and how they may play a central role in glioma tumorigenesis. Among the many molecular interactions that PrP physiologically performs, it appears that processes shared with autophagy activity are those most implicated in glial tumor carcinogeneses such as activity on MAP kinases, PI3K, and mTOR. This work can be supportive and valuable as a basis for further future studies on this topic.

Oligomeropathies, inflammation and prion protein binding.

The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic β amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both β amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with β-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.

Role of cellular prion protein in splenic CD4+ T cell differentiation in cerebral ischaemic/reperfusion.

ObjectiveCellular prion protein (PrPC), the primary form of prion diseases pathogen, has received increasing attention for its protective effect against ischaemic stroke. Little is known about its role in peripheral immune responses after cerebral ischaemia/reperfusion (I/R) injury. This study is to detect the variation of splenic CD4+ T lymphocytes differentiation and the concentration of inflammatory cytokines after murine cerebral I/R injury in the context of PRNP expression as well as its influence on the ischaemic neuronal apoptosis.MethodsWe established the cerebral ischaemic murine model of different PRNP genotypes. We detected the percentage of splenic CD4+PrPC+ T cells of PRNP wild‐type mice and the ratio of splenic Th1/2/17 lymphocytes of mice of different PRNP expression. The relevant inflammatory cytokines were then measured. Oxygen glucose deprivation/reperfusion (OGD/R) HT22 mouse hippocampal neurons were co‐cultured with the T‐cell‐conditioned medium harvested from the spleen of modelled mice and then the neuronal apoptosis was detected.ResultsCD4+ PrPC+ T lymphocytes in wild‐type mice elevated after MCAO/R. PRNP expression deficiency led to an elevation of Th1/17 phenotypes and the promotion of pro‐inflammatory cytokines, while PRNP overexpression led to the elevation of Th2 phenotype and upregulation of anti‐inflammatory cytokines. In addition, PrPC‐overexpressed CD4+T cells weakened the apoptosis of OGD/R HT‐22 murine hippocampal neurons caused by MCAO/R CD4+ T‐cell‐conditioned medium, while PrPC deficiency enhanced apoptosis.InterpretationPrPC works as a neuron protector in the CNS when I/R injury occurs and affects the peripheral immune responses and defends against stroke‐induced neuronal apoptosis.

The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target.

Prion protein has two isoforms including cellular prion protein (PrPC) and scrapie prion protein (PrPSc). PrPSc is the pathological aggregated form of prion protein and it plays an important role in neurodegenerative diseases. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein that can attach to a membrane. Its expression begins at embryogenesis and reaches the highest level in adulthood. PrPC is expressed in the neurons of the nervous system as well as other peripheral organs. Studies in recent years have disclosed the involvement of PrPC in various aspects of cancer biology. In this review, we provide an overview of the current understanding of the roles of PrPC in proliferation, cell survival, invasion/metastasis, and stem cells of cancer cells, as well as its role as a potential therapeutic target.

Prion Protein of Extracellular Vesicle Regulates the Progression of Colorectal Cancer.

Simple SummaryCellular prion protein (PrPC) are overexpressed in cancers and related to cancer proliferation, invasion, metastasis, and drug resistance. The aim of our study was to investigate the role of PrPC-expressing exosomes regulating the colorectal cancer cells (CRC) behavior and tumor progression. We confirmed the increased sphere formation, expression of cancer initiating genes, motility, and tumor growth by hypoxic exosomes. Also, PrPC-expressing exosomes induced the microenvironment of metastasis via increase of endothelial permeability and angiogenic cytokine secretion. The treatment of anti-PrPC and 5-fluorouracil decreased the tumor progression. Targeting PrPC is an effective therapeutic strategy in cancer therapy.Colorectal cancer (CRC) is one of the leading causes of cancer-related death due to its aggressive metastasis in later stages. Although there is a growing interest in the tumorigenic role of cellular prion protein (PrPC) in the process of metastasis, the precise mechanism behind the cellular communication involving prion proteins remains poorly understood. This study found that hypoxic tumor microenvironment increased the PrPC-expressing exosomes from CRC, and these exosomes regulate the CRC cell behavior and tumor progression depending on the expression of PrPC. Hypoxic exosomes from CRC cells promoted sphere formation, the expression of tumor-inducing genes, migration, invasion, and tumor growth. Furthermore, these exosomes increased endothelial permeability, migration, invasion, and angiogenic cytokine secretion. These effects were associated with PrPC expression. Application of anti-PrPC antibody with 5-fluorouracil significantly suppressed the CRC progression in a murine xenograft model. Taken together, these findings indicate that PrP-expressing exosomes secreted by hypoxic CRC cells are a key factor in the tumorigenic CRC-to-CRC and CRC-to-endothelial cell communication. Significance: These findings suggest that inhibiting PrPC in hypoxic exosomes during chemotherapy may be an effective therapeutic strategy in colorectal cancer.

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer.

Simple SummaryAside from its well-established role in prion disorders, in the last decades the significance of cellular prion protein (PrPC) expression in human cancers has attracted great attention. An extensive body of work provided evidence that PrPC contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPC over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma, osteosarcoma, breast, gastric, and colorectal cancers, and primary brain tumors as well. According to consensus, increased levels of PrPC endow CSCs with self-renewal, proliferative, migratory, and invasive capacities, along with increased resistance to anti-cancer agents. In addition, increasing evidence demonstrates that PrPc also participates in multi-protein complexes to modulate the oncogenic properties of CSCs, thus sustaining tumorigenesis. Therefore, strategies aimed at targeting PrPC and/or PrPC-organized complexes could be a promising approach for anti-cancer therapy.Cellular prion protein (PrPC) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrPC also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrPSc). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrPC in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrPC in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrPC on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrPC and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrPC beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.

Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process.

The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells.

The role of cellular prion protein in lipid metabolism in the liver

ABSTRACT Cellular prion protein (PrPC) is a plasma membrane glycophosphatidylinositol-anchored protein and it is involved in multiple functions, including neuroprotection and oxidative stress. So far, most of the PrPC functional research is done in neuronal tissue or cell lines; the role of PrPC in non-neuronal tissues such as liver is only poorly understood. To characterize the role of PrPC in the liver, a proteomics approach was applied in the liver tissue of PrPC knockout mice. The proteome analysis and biochemical validations showed an excessive fat accumulation in the liver of PrPC knockout mice with a change in mRNA expression of genes linked to lipid metabolism. In addition, the higher Bax to Bcl2 ratio, up-regulation of tgfb1 mRNA expression in PrPC knockout mice liver, further showed the evidences of metabolic disease. Over-expression of PrPC in fatty acid-treated AML12 hepatic cell line caused a reduction in excessive intracellular fat accumulation; shows association of PrPC levels and lipid metabolism. Therefore, based on observation of excessive fat globules in the liver of ageing PrPC knockout mice and the reduction of fat accumulation in AML12 cell line with PrPC over-expression, the role of PrPC in lipid metabolism is described.

Emerging Role of Cellular Prion Protein in the Maintenance and Expansion of Glioma Stem Cells.

Cellular prion protein (PrPC) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrPSc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrPC. Although PrPC ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrPC stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrPC activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrPC acts as scaffold to stabilize the binding between different membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrPC expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrPC overexpression in cancer stem cells (CSCs) from different tumors, including gliomas—the most malignant brain tumors—is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrPC role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrPC contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity.

Low-Field Magnetic Stimulation Restores Cognitive and Motor Functions in the Mouse Model of Repeated Traumatic Brain Injury: Role of Cellular Prion Protein.

Traumatic brain injury (TBI)/concussion is a growing epidemic throughout the world. Memory and neurobehavioral dysfunctions are among the sequelae of TBI. Dislodgement of cellular prion protein (PrPc) and disruption of circadian rhythm have been linked to TBI. Low-field magnetic stimulation (LFMS) is a new noninvasive repetitive transcranial magnetic stimulation (rTMS) technique that generates diffused and low-intensity magnetic stimulation to deep cortical and subcortical areas. The role of LFMS on PrPc, proteins related to the circadian rhythm, and behavior alterations in a repeated TBI mouse model were studied in the present study. TBI was induced to the mice (right hemisphere) using weight-drop method, once daily for 3 days. LFMS treatment was given for 20 min once daily for 4 days (immediately after each TBI induction). The results showed that LFMS-treated TBI mice significantly improved cognitive and motor function as evidenced by open field exploration, rotarod, and novel location recognition tasks. In addition, a significant increase in PrPc and decreased glial fibrillary acidic protein levels were observed in cortical and hippocampal regions of LFMS-treated TBI mice brain compared with sham-treated TBI mice, while neuronal nuclei level was significantly increased in cortical region. In LFMS-treated mice, a decrease in proteins related to circadian rhythm were observed, compared with sham-treated TBI mice. The results obtained from the study demonstrated the neuroprotective effect of LFMS, which may be through regulating PrPc and/or proteins related to circadian rhythm. Thus, the present study suggests that LFMS may improve the subject's neurological condition following TBI.

Cellular Prion Protein Mediates the Disruption of Hippocampal Synaptic Plasticity by Soluble Tau In Vivo.

Intracellular neurofibrillary tangles (NFTs) composed of tau protein are a neuropathological hallmark of several neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). For some time NFTs were considered the primary cause of synaptic dysfunction and neuronal death, however, more recent evidence suggests that soluble aggregates of tau are key drivers of disease. Here we investigated the effect of different tau species on synaptic plasticity in the male rat hippocampus in vivo Intracerebroventricular injection of soluble aggregates formed from either wild-type or P301S human recombinant tau potently inhibited hippocampal long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, tau monomers and fibrils appeared inactive. Neither baseline synaptic transmission, paired-pulse facilitation nor burst response during high-frequency conditioning stimulation was affected by the soluble tau aggregates. Similarly, certain AD brain soluble extracts inhibited LTP in a tau-dependent manner that was abrogated by either immunodepletion with, or coinjection of, a mid-region anti-tau monoclonal antibody (mAb), Tau5. Importantly, this tau-mediated block of LTP was prevented by administration of mAbs selective for the prion protein (PrP). Specifically, mAbs to both the mid-region (6D11) and N-terminus (MI-0131) of PrP prevented inhibition of LTP by both recombinant and brain-derived tau. These findings indicate that PrP is a mediator of tau-induced synaptic dysfunction.SIGNIFICANCE STATEMENT Here we report that certain soluble forms of tau selectively disrupt synaptic plasticity in the live rat hippocampus. Further, we show that monoclonal antibodies to cellular prion protein abrogate the impairment of long-term potentiation caused both by recombinant and Alzheimer's disease brain-derived soluble tau. These findings support a critical role for cellular prion protein in the deleterious synaptic actions of extracellular soluble tau in tauopathies, including Alzheimer's disease. Thus, approaches targeting cellular prion protein, or downstream pathways, might provide an effective strategy for developing therapeutics.

Prion protein is essential for the RE1 silencing transcription factor (REST)-dependent developmental switch in synaptic NMDA receptors

It is important that the correct amounts of GluN2 subunits are maintained, as they determine NMDAR functional properties, which are crucial to neuronal communication, synaptogenesis and cognitive function. The transcriptional repressor RE1 silencing transcription factor (REST) is critical for the postnatal developmental switch in NMDARs. However, the mechanisms triggering REST and the link between NMDARs and REST are unclear. Here we show a new physiological essential role for cellular prion protein (PrPC) in REST-dependent homeostasis and the developmental switch of NMDARs. REST and REST-associated proteins were overactivated in the hippocampi of Prnp knockout mice (Prnp0/0) compared with wild-type Prnp (Prnp+/+) mice. This coincided with the disruption of the normal developmental switch from GluN2B-to-GluN2A in vivo. PrPC co-located with REST under physiological environments and mediated the translocation of REST in conditioners of NMDARs in vitro in Prnp+/+ hippocampal neurons. Regardless of whether REST was knocked down or overexpressed, deletion of PrPC not only disrupted REST-mediated distribution of mitochondria, but also prevented REST-regulated expression of GluN2B and GluN2A in Prnp0/0. Importantly, these effects were rescued after overexpression of full-length PrPC through restoration of NMDAR2 subunits and their distributions in dendritic processes in Prnp0/0. Consistently, knockdown of PrPC in Prnp+/+ had a similar effect on Prnp0/0. Furthermore, PrPC colocalized with both GluN2B and GluN2A in Prnp+/+. For the first time, we demonstrate that PrPC is essential for REST-regulated NMDARs. Confirming the regulation of NMDAR-modulating mechanisms could provide novel therapeutic targets against dysfunctions of glutamatergic transmission in the nervous system.

A Role for Cellular Prion Protein in Late-Onset Alzheimer's Disease: Evidence from Preclinical Studies.

Alzheimer's disease (AD), the most prevalent form of dementia, affects 1 in 9 individuals >65 years old ([Alzheimer's Association, 2016][1]). Cognitive decline is the most distinctive symptom of AD, and it strongly correlates with synapse loss ([Masliah et al., 1990][2]; [Terry et al., 1991][3]).

Protective role of cellular prion protein against TNF\u03b1-mediated inflammation through TACE \u03b1-secretase

Although cellular prion protein PrPC is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrPC displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrPC coupling to the NADPH oxidase-TACE α-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNFα receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNFα. We further show that PrPC expression is necessary for TACE α-secretase to stay at the plasma membrane in an active state for TNFR shedding. Such PrPC control of TACE localization depends on PrPC modulation of β1 integrin signaling and downstream activation of ROCK-I and PDK1 kinases. Loss of PrPC provokes TACE internalization, which in turn cancels TACE-mediated cleavage of TNFR and renders PrPC-depleted neuronal cells as well as PrPC knockout mice highly vulnerable to pro-inflammatory TNFα insult. Our work provides the prime evidence that in an inflammatory context PrPC adjusts the response of neuronal cells targeted by TNFα through TACE α-secretase. Our data also support the view that abnormal TACE trafficking and activity in prion diseases originate from a-loss-of-PrPC cytoprotective function.

Dual role of cellular prion protein in normal host and Alzheimer’s disease

Using PrPC-knockout cell lines, it has been shown that the inhibition of apoptosis through STI1 is mediated by PrPC-dependent SOD activation. Antioxidant PrPC may contribute to suppression of inflammasome activation. PrPC is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. Recently several reports have shown that PrPC participates in trans-membrane signaling processes associated with hematopoietic stem cell replication and neuronal differentiation. In another role, PrPC also tends to function as a neurotoxic protein. Aβ oligomer, which is associated with neurodegeneration in Alzheimer’s disease (AD), has also been reported to act as a ligand of PrPC. However, the physiological role of PrPC as an Aβ42-binding protein is not clear. Actually, PrPC is critical in Aβ42-mediated autophagy in neurons. PrPC shows a beneficial role in lipid rafts to promote autophagy. Further search for PrPC-interaction molecules using Prnp−/− mice and various types of Prnp−/− cell lines under various conditions may elucidate other important PrPC important functions.

Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy

Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better insights into changes in brain metabolism. We performed cytokine profiling and measured levels of the cellular prion protein (PrPC) in serum and cerebrospinal fluid (CSF) samples from patients with VD and with vascular encephalopathy (VE). Significant changes were observed for interleukin (IL)-1β, IL-4, IL-5, tumor necrosis factor alpha, interferon gamma, granulocyte-colony stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta in serum and for IL-6 and granulocyte macrophage colony-stimulating factor in CSF of VD and VE patients, suggesting that most of immune markers depend on vascular lesions, while only IL-6 was related to dementia. In VD patients, the severity of dementia as defined by the Mini-Mental Status Test or Cambridge Cognitive Examination battery test was significantly correlated with the levels of IL-8 (CSF) and macrophage inflammatory protein 1 beta (serum and CSF). Additionally, in CSF of VD patients, our data revealed a correlation between immune and neurodegenerative marker proteins. Both indicate an association of neuroinflammation and cognitive decline. Levels of PrPC were regulated differentially in VD and VE patients compared with Alzheimer's disease patients and controls. Moreover, we observed a significant negative correlation between cytokine levels and PrPC in VD patients in CSF and serum, as well as a correlation between PrPC expression with levels of neurodegenerative marker proteins in CSF (in VD and VE patients). Our data suggest that immunological modifiers play a role in VD and VE patients and provide evidence for an association of PrPC with immune and neurodegenerative markers.

Developmental expression of cellular prion protein and apoptotic molecules in the rat cerebellum: Effects of platinum compounds

Programmed cell death is regulated by prototypes of a large family of Bcl-2-like proteins such as Bax and Bcl-2. A neuroprotective role for cellular prion protein (PrPc) on programmed cell death has been reported, although the cytosolic accumulation of PrPc correlates with toxicity and death of some neurons by apoptosis. In order to understand the signalling function of PrPc in promoting survival or suppressing cell death, we analyzed the expression and co-localization of PrPc, Bax and Bcl-2 proteins in the developing cerebellum of rats treated at PD10 (postnatal day 10) with the chemotherapeutic drug cisplatin (cisPt) or the new platinum (Pt) compound [Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS). Differences in the expression of PrPc, Bax and Bcl-2 were found in proliferating cells and immature Purkinje neurons. One day after administration (PD11), cisPt markedly increased the apoptosis of the proliferating cells of the EGL (external granular layer); at the same time, several apoptotic bodies with strong Bax immunoreactivity were noticed. After PtAcacDMS, changes in PrPc and apoptotic proteins, with respect to the controls, were found but Bax immunopositive apoptotic bodies were not detectable, which could mean that apoptotic cell death of proliferating cells is preserved. Co-localization was clearly detected in the Purkinje cell population and may explain better the mechanisms by which PrPc and the apoptotic proteins function, and particularly the role of PrPc. Considering the reactivity of Purkinje neurons to these proteins at PD11 and Pd17, at least PrPc expression increased after cisPt and PtAcacDMS treatments or, if PrPc decreased, balanced itself with Bcl-2. The noteworthiness of this finding is that it emphasizes that most of the post-mitotic Purkinje cells need to be rescued, otherwise they undergo degeneration and are not replaced. Based on the effects of both Pt compounds on Purkinje cell differentiation, it should be emphasized that PrPc, together with the synergistic action of the co-localized anti-apoptotic protein, acts as a neuroprotective protein countering cytotoxicity in the postnatal critical phases of cerebellum development.

Association of prion protein with cognitive functioning in humans

ObjectivesRecent animal studies have suggested a key role for cellular prion protein (PrPc) in the pathological consequences of amyloid plaque formation, the hallmark of Alzheimer's disease. This epidemiological study investigated whether serum concentrations of PrPc are associated with cognitive functioning in humans. Design, Setting, ParticipantsCross-sectional study of 1,322 participants from the elderly general population in Germany, aged 65+ years at baseline (2000–2002). MeasurementsCognitive functioning was assessed by the COGTEL phone interview 5years after baseline. Serum PrPc was determined by a commercial immunoassay. ResultsIn multiple linear regression adjusted for important confounders, subjects in higher PrPc quintiles appeared to have lower cognitive functioning scores than those in the lowest PrPc quintile. Spline regression suggested pronounced non-linearity with an inverse association between PrPc and cognitive functioning levelling off beyond median PrPc. Cognitive subdomain-specific models produced somewhat heterogeneous results. ConclusionThe findings are suggestive of an independent association of PrPc with cognitive functioning in humans. Confirmatory and longitudinal studies are needed to elucidate the potential of PrPc for applications in early risk stratification for cognitive impairment.

Unaltered prion protein expression in Alzheimer disease patients

The suggested role of cellular prion protein (PrPC) in mediating the toxic effects of oligomeric amyloid β peptide (Aβ) in Alzheimer disease (AD) is controversial. To address the hypothesis that variable PrPC expression is involved in AD pathogenesis, we analyzed PrPC expression in the frontal and temporal cortices and hippocampus of individuals with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), mild AD (mAD), and AD. We found that PrPC expression in all brain regions was not significantly altered among the various patient groups. In addition, PrPC levels in all groups did not correlate with expression of methionine (M) or valine (V) at codon 129 of the PrP gene, a polymorphism that has been linked in some studies to increased risk for AD, and which occurs in close proximity to the proposed binding region for the oligomeric Aβ peptide. Our results indicate that, if PrPC is involved in mediating the toxic effects of the oligomeric Aβ peptide, these effects occur independently of steady state levels of PrP or the codon 129 polymorphism.