Machine Learning Support for Decision-Making in Kidney Transplantation: Step-by-step Development of a Technological Solution.

BACKGROUND: Kidney transplantation is the preferred treatment option for patients with end-stage renal disease. To maximize patient and graft survival, the allocation of donor organs to potential recipients requires careful consideration. OBJECTIVE: This study aimed to develop an innovative technological solution to enable better prediction of kidney transplant survival for each potential donor-recipient pair. METHODS: We used deidentified data on past organ donors, recipients, and transplant outcomes in the United States from the Scientific Registry of Transplant Recipients. To predict transplant outcomes for potential donor-recipient pairs, we used several survival analysis models, including regression analysis (Cox proportional hazards), random survival forests, and several artificial neural networks (DeepSurv, DeepHit, and recurrent neural network [RNN]). We evaluated the performance of each model in terms of its ability to predict the probability of graft survival after kidney transplantation from deceased donors. Three metrics were used: the C-index, integrated Brier score, and integrated calibration index, along with calibration plots. RESULTS: On the basis of the C-index metrics, the neural network-based models (DeepSurv, DeepHit, and RNN) had better discriminative ability than the Cox model and random survival forest model (0.650, 0.661, and 0.659 vs 0.646 and 0.644, respectively). The proposed RNN model offered a compromise between the good discriminative ability and calibration and was implemented in a technological solution of technology readiness level 4. CONCLUSIONS: Our technological solution based on the RNN model can effectively predict kidney transplant survival and provide support for medical professionals and candidate recipients in determining the most optimal donor-recipient pair.

The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons.

Highly organized circuits of enteric neurons are required for the regulation of gastrointestinal functions, such as peristaltism or migrating motor complex. However, the factors and molecular mechanisms that regulate the connectivity of enteric neurons and their assembly into functional neuronal networks are largely unknown. A better understanding of the mechanisms by which neurotrophic factors regulate this enteric neuron circuitry is paramount to understanding enteric nervous system (ENS) physiology. EphB2, a receptor tyrosine kinase, is essential for neuronal connectivity and plasticity in the brain, but so far its presence and function in the ENS remain largely unexplored. Here we report that EphB2 is expressed preferentially by enteric neurons relative to glial cells throughout the gut in rats. We show that in primary enteric neurons, activation of EphB2 by its natural ligand ephrinB2 engages ERK signaling pathways. Long-term activation with ephrinB2 decreases EphB2 expression and reduces molecular and functional connectivity in enteric neurons without affecting neuronal density, ganglionic fiber bundles, or overall neuronal morphology. This is highlighted by a loss of neuronal plasticity markers such as synapsin I, PSD95, and synaptophysin, and a decrease of spontaneous miniature synaptic currents. Together, these data identify a critical role for EphB2 in the ENS and reveal a unique EphB2-mediated molecular program of synapse regulation in enteric neurons.

Genomic investigation of atypical malaria cases in Kanel, northern Senegal.

BACKGROUND: The diagnosis of malaria cases in regions where the malaria burden has decreased significantly and prevalence is very low is more challenging, in part because of reduced clinical presumption of malaria. The appearance of a cluster of malaria cases with atypical symptoms in Mbounguiel, a village in northern Senegal where malaria transmission is low, in September 2018 exemplifies this scenario. The collaboration between the National Malaria Control Programme (NMCP) at the Senegal Ministry of Health and the Laboratory of Parasitology and Mycology at Cheikh Anta Diop University worked together to evaluate this cluster of malaria cases using molecular and serological tools. METHODS: Malaria cases were diagnosed primarily by rapid diagnostic test (RDT), and confirmed by photo-induced electron transfer-polymerase chain reaction (PET-PCR). 24 single nucleotide polymorphisms (SNPs) barcoding was used for Plasmodium falciparum genotyping. Unbiased metagenomic sequencing and Luminex-based multi-pathogen antibody and antigen profiling were used to assess exposure to other pathogens. RESULTS: Nine patients, of 15 suspected cases, were evaluated, and all nine samples were found to be positive for P. falciparum only. The 24 SNPs molecular barcode showed the predominance of polygenomic infections, with identifiable strains being different from one another. All patients tested positive for the P. falciparum antigens. No other pathogenic infection was detected by either the serological panel or metagenomic sequencing. CONCLUSIONS: This work, undertaken locally within Senegal as a collaboration between the NMCP and a research laboratory at University of Cheikh Anta Diop (UCAD) revealed that a cluster of malaria cases were caused by different strains of P. falciparum. The public health response in real time demonstrates the value of local molecular and genomics capacity in affected countries for disease control and elimination.

Correction to: Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

An amendment to this paper has been published and can be accessed via the original article.

Genetic evidence for imported malaria and local transmission in Richard Toll, Senegal.

BACKGROUND: Malaria elimination efforts can be undermined by imported malaria infections. Imported infections are classified based on travel history. METHODS: A genetic strategy was applied to better understand the contribution of imported infections and to test for local transmission in the very low prevalence region of Richard Toll, Senegal. RESULTS: Genetic relatedness analysis, based upon molecular barcode genotyping data derived from diagnostic material, provided evidence for both imported infections and ongoing local transmission in Richard Toll. Evidence for imported malaria included finding that a large proportion of Richard Toll parasites were genetically related to parasites from Thiès, Senegal, a region of moderate transmission with extensive available genotyping data. Evidence for ongoing local transmission included finding parasites of identical genotype that persisted across multiple transmission seasons as well as enrichment of highly related infections within the households of non-travellers compared to travellers. CONCLUSIONS: These data indicate that, while a large number of infections may have been imported, there remains ongoing local malaria transmission in Richard Toll. These proof-of-concept findings underscore the value of genetic data to identify parasite relatedness and patterns of transmission to inform optimal intervention selection and placement.

Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

BACKGROUND: Population-wide interventions using malaria testing and treatment might decrease the reservoir of Plasmodium falciparum infection and accelerate towards elimination. Questions remain about their effectiveness and evidence from different transmission settings is needed. METHODS: A pilot quasi-experimental study to evaluate a package of population-wide test and treat interventions was conducted in six health facility catchment areas (HFCA) in the districts of Kanel, Linguère, and Ranérou (Senegal). Seven adjacent HFCAs were selected as comparison. Villages within the intervention HFCAs were stratified according to the 2013 incidences of passively detected malaria cases, and those with an incidence ≥ 15 cases/1000/year were targeted for a mass test and treat (MTAT) in September 2014. All households were visited, all consenting individuals were tested with a rapid diagnostic test (RDT), and, if positive, treated with dihydroartemisinin-piperaquine. This was followed by weekly screening, testing and treatment of fever cases (PECADOM++) until the end of the transmission season in January 2015. Villages with lower incidence received only PECADOM++ or case investigation. To evaluate the impact of the interventions over that transmission season, the incidence of passively detected, RDT-confirmed malaria cases was compared between the intervention and comparison groups with a difference-in-difference analysis using negative binomial regression with random effects on HFCA. RESULTS: During MTAT, 89% (2225/2503) of households were visited and 86% (18,992/22,170) of individuals were tested, for a combined 77% effective coverage. Among those tested, 291 (1.5%) were RDT positive (range 0-10.8 by village), of whom 82% were < 20 years old and 70% were afebrile. During the PECADOM++ 40,002 visits were conducted to find 2784 individuals reporting fever, with an RDT positivity of 6.5% (170/2612). The combination of interventions resulted in an estimated 38% larger decrease in malaria case incidence in the intervention compared to the comparison group (adjusted incidence risk ratio = 0.62, 95% CI 0.45-0.84, p = 0.002). The cost of the MTAT was $14.3 per person. CONCLUSIONS: It was operationally feasible to conduct MTAT and PECADOM++ with high coverage, although PECADOM++ was not an efficient strategy to complement MTAT. The modest impact of the intervention package suggests a need for alternative or complementary strategies.

Proactive community case management in Senegal 2014-2016: a case study in maximizing the impact of community case management of malaria.

The Senegal National Malaria Control Programme (NMCP) introduced home-based malaria management for all ages, with diagnosis by rapid diagnostic test (RDT) and treatment with artemisinin-based combination therapy (ACT) in 2008, expanding to over 2000 villages nationwide by 2014. With prise en charge à domicile (PECADOM), community health workers (CHWs) were available for community members to seek care, but did not actively visit households to find cases. A trial of a proactive model (PECADOM Plus), in which CHWs visited all households in their village weekly during transmission season to identify fever cases and offer case management, in addition to availability during the week for home-based management, found that CHWs detected and treated more cases in intervention villages, while the number of cases detected weekly decreased over the transmission season. The NMCP scaled PECADOM Plus to three districts in 2014 (132 villages), to a total of six districts in 2015 (246 villages), and to a total of 16 districts in 2016 (708 villages). A narrative case study with programmatic results is presented. During active sweeps over approximately 20 weeks, CHWs tested a mean of 77 patients per CHW in 2014, 89 patients per CHW in 2015, and 90 patients per CHW in 2016, and diagnosed a mean of 61, 61 and 43 patients with malaria per CHW in 2014, 2015 and 2016, respectively. The number of patients who sought care between sweeps increased, with a 104% increase in the number of RDTs performed and a 77% increase in the number of positive tests and patients treated with ACT during passive case detection. While the number of CHWs increased 7%, the number of patients receiving an RDT increased by 307% and the number of malaria cases detected and treated by CHWs increased 274%, from the year prior to PECADOM Plus introduction to its first year of implementation. Based on these results, approximately 700 additional CHWs in 24 new districts were added in 2017. This case study describes the process, results and lessons learned from Senegal's implementation of PECADOM Plus, as well as guidance for other programmes considering introduction of this innovative strategy.

Assessing whether universal coverage with insecticide-treated nets has been achieved: is the right indicator being used?

BACKGROUND/METHODS: Insecticide-treated nets (ITNs) are the primary tool for malaria vector control in sub-Saharan Africa, and have been responsible for an estimated two-thirds of the reduction in the global burden of malaria in recent years. While the ultimate goal is high levels of ITN use to confer protection against infected mosquitoes, it is widely accepted that ITN use must be understood in the context of ITN availability. However, despite nearly a decade of universal coverage campaigns, no country has achieved a measured level of 80% of households owning 1 ITN for 2 people in a national survey. Eighty-six public datasets from 33 countries in sub-Saharan Africa (2005-2017) were used to explore the causes of failure to achieve universal coverage at the household level, understand the relationships between the various ITN indicators, and further define their respective programmatic utility. RESULTS: The proportion of households owning 1 ITN for 2 people did not exceed 60% at the national level in any survey, except in Uganda's 2014 Malaria Indicator Survey (MIS). At 80% population ITN access, the expected proportion of households with 1 ITN for 2 people is only 60% (p = 0.003 R2 = 0.92), because individuals in households with some but not enough ITNs are captured as having access, but the household does not qualify as having 1 ITN for 2 people. Among households with 7-9 people, mean population ITN access was 41.0% (95% CI 36.5-45.6), whereas only 6.2% (95% CI 4.0-8.3) of these same households owned at least 1 ITN for 2 people. On average, 60% of the individual protection measured by the population access indicator is obscured when focus is put on the household "universal coverage" indicator. The practice of limiting households to a maximum number of ITNs in mass campaigns severely restricts the ability of large households to obtain enough ITNs for their entire family. CONCLUSIONS: The two household-level indicators-one representing minimal coverage, the other only 'universal' coverage-provide an incomplete and potentially misleading picture of personal protection and the success of an ITN distribution programme. Under current ITN distribution strategies, the global malaria community cannot expect countries to reach 80% of households owning 1 ITN for 2 people at a national level. When programmes assess the success of ITN distribution activities, population access to ITNs should be considered as the better indicator of "universal coverage," because it is based on people as the unit of analysis.

How Far Are We from Reaching Universal Malaria Testing of All Fever Cases?

Universal malaria diagnostic testing of all fever cases is the first step in correct malaria case management. However, monitoring adherence to universal testing is complicated by unreliable recording and reporting of the true number of fever cases. We searched the literature to obtain gold-standard estimates for the proportion of patients attending outpatient clinics in sub-Saharan Africa with malarial and non-malarial febrile illness. To correct for differences in malaria transmission, we calculated the proportion of patients with fever after excluding confirmed malaria cases. Next, we analyzed routine data from Guinea and Senegal to calculate the proportion of outpatients tested after exclusion of confirmed malaria cases from the numerator and denominator. From 12 health facility surveys in sub-Saharan Africa with gold-standard fever screening, the median proportion of febrile illness among outpatients after exclusion of confirmed malaria fevers was 57% (range: 46-80%). Analysis of routine data after exclusion of confirmed malaria cases demonstrated much lower testing proportions of 23% (Guinea) and 13% (Senegal). There was substantial spatial and temporal heterogeneity in this testing proportion, and testing in Senegal was correlated with malaria season. Given the evidence from gold-standard surveys that at least 50% of non-malaria consultations in sub-Saharan Africa are for febrile illness, it appears that a substantial proportion of patients with fever are not tested for malaria in health facilities when considering routine data. Tracking the proportion of patients tested for malaria after exclusion of the confirmed malaria cases could allow programs to make inferences about malaria testing practices using routine data.

Declines in Malaria Burden and All-Cause Child Mortality following Increases in Control Interventions in Senegal, 2005-2010.

Malaria is endemic in Senegal. The national malaria control strategy focuses on achieving universal coverage for major interventions, with a goal of reaching preelimination status by 2018. Senegal began distribution of insecticide-treated nets (ITNs) and introduced artemisinin-based combination therapy in 2006, then introduced rapid diagnostic tests in 2007. We evaluated the impact of these efforts using a plausibility design based on malaria's contribution to all-cause under-five mortality (ACCM) and considering other contextual factors which may influence ACCM. Between 2005 and 2010, household ownership of ITNs increased from 20% to 63%, and the proportion of people sleeping under an ITN the night prior to the survey increased from 6% to 29%. Malaria parasite prevalence declined from 6% to 3% from 2008 to 2010 among children under five. Some nonmalaria indicators of child health improved, for example, increase of complete vaccination coverage from 58% to 64%; however, nutritional indicators deteriorated, with an increase in stunting from 16% to 26%. Although economic indicators improved, environmental conditions favored an increase in malaria transmission. ACCM decreased 40% between 2005 and 2010, from 121 (95% confidence interval [CI] 113-129) to 72 (95% CI 66-77) per 1,000, and declines were greater among age groups, epidemiologic zones, and wealth quintiles most at risk for malaria. After considering coverage of malaria interventions, trends in malaria morbidity, effects of contextual factors, and trends in ACCM, it is plausible that malaria control interventions contributed to a reduction in malaria mortality and to the impressive gains in child survival in Senegal.

Comparison of Malaria Simulations Driven by Meteorological Observations and Reanalysis Products in Senegal.

The analysis of the spatial and temporal variability of climate parameters is crucial to study the impact of climate-sensitive vector-borne diseases such as malaria. The use of malaria models is an alternative way of producing potential malaria historical data for Senegal due to the lack of reliable observations for malaria outbreaks over a long time period. Consequently, here we use the Liverpool Malaria Model (LMM), driven by different climatic datasets, in order to study and validate simulated malaria parameters over Senegal. The findings confirm that the risk of malaria transmission is mainly linked to climate variables such as rainfall and temperature as well as specific landscape characteristics. For the whole of Senegal, a lag of two months is generally observed between the peak of rainfall in August and the maximum number of reported malaria cases in October. The malaria transmission season usually takes place from September to November, corresponding to the second peak of temperature occurring in October. Observed malaria data from the Programme National de Lutte contre le Paludisme (PNLP, National Malaria control Programme in Senegal) and outputs from the meteorological data used in this study were compared. The malaria model outputs present some consistencies with observed malaria dynamics over Senegal, and further allow the exploration of simulations performed with reanalysis data sets over a longer time period. The simulated malaria risk significantly decreased during the 1970s and 1980s over Senegal. This result is consistent with the observed decrease of malaria vectors and malaria cases reported by field entomologists and clinicians in the literature. The main differences between model outputs and observations regard amplitude, but can be related not only to reanalysis deficiencies but also to other environmental and socio-economic factors that are not included in this mechanistic malaria model framework. The present study can be considered as a validation of the reliability of reanalysis to be used as inputs for the calculation of malaria parameters in the Sahel using dynamical malaria models.

Assessment of the utility of a symptom-based algorithm for identifying febrile patients for malaria diagnostic testing in Senegal.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) enable point-of-care testing to be nearly as sensitive and specific as reference microscopy. The Senegal National Malaria Control Programme introduced RDTs in 2007, along with a case management algorithm for uncomplicated febrile illness, in which the first step stipulates that if a febrile patient of any age has symptoms indicative of febrile illness other than malaria (e.g., cough or rash), they would not be tested for malaria, but treated for the apparent illness and receive an RDT for malaria only if they returned in 48 h without improvement. METHODS: A year-long study in 16 health posts was conducted to determine the algorithm's capacity to identify patients with Plasmodium falciparum infection identifiable by RDT. Health post personnel enrolled patients of all ages with fever (≥37.5 °C) or history of fever in the previous 2 days. After clinical assessment, a nurse staffing the health post determined whether a patient should receive an RDT according to the diagnostic algorithm, but performed an RDT for all enrolled patients. RESULTS: Over 1 year, 6039 patients were enrolled and 58% (3483) were determined to require an RDT according to the algorithm. Overall, 23% (1373/6039) had a positive RDT, 34% (1130/3376) during rainy season and 9% (243/2661) during dry season. The first step of the algorithm identified only 78% of patients with a positive RDT, varying by transmission season (rainy 80%, dry 70%), malaria transmission zone (high 75%, low 95%), and age group (under 5 years 68%, 5 years and older 84%). CONCLUSIONS: In all but the lowest malaria transmission zone, use of the algorithm excludes an unacceptably large proportion of patients with malaria from receiving an RDT at their first visit, denying them timely diagnosis and treatment. While the algorithm was adopted within a context of malaria control and scarce resources, with the goal of treating patients with symptomatic malaria, Senegal has now adopted a policy of universal diagnosis of patients with fever or history of fever. In addition, in the current context of malaria elimination, the paradigm of case management needs to shift towards the identification and treatment of all patients with malaria infection.

The transcription factor XBP1 in memory and cognition: Implications in Alzheimer disease.

X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein regulating many physiological functions, including immune system, inflammatory responses, and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays important roles in pathological settings since its activity as transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration, and diabetes. Here we provide an overview on recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases with emphasis on Alzheimer disease.

Eph receptors: new players in Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is devastating and leads to permanent losses of memory and other cognitive functions. Although recent genetic evidences strongly argue for a causative role of Aß in AD onset and progression (Jonsson et al., 2012), its role in AD etiology remains a matter of debate. However, even if not the sole culprit or pathological trigger, genetic and anatomical evidences in conjunction with numerous pharmacological studies, suggest that Aß peptides, at least contribute to the disease. How Aß contributes to memory loss remains largely unknown. Soluble Aß species referred to as Aß oligomers have been shown to be neurotoxic and induce network failure and cognitive deficits in animal models of the disease. In recent years, several proteins were described as potential Aß oligomers receptors, amongst which are the receptor tyrosine kinases of Eph family. These receptors together with their natural ligands referred to as ephrins have been involved in a plethora of physiological and pathological processes, including embryonic neurogenesis, learning and memory, diabetes, cancers and anxiety. Here we review recent discoveries on Eph receptors-mediated protection against Aß oligomers neurotoxicity as well as their potential as therapeutic targets in AD pathogenesis.

Climate and health: observation and modeling of malaria in the Ferlo (Senegal).

The aim of this work, undertaken in the framework of QWeCI (Quantifying Weather and Climate Impacts on health in the developing countries) project, is to study how climate variability could influence malaria seasonal incidence. It will also assess the evolution of vector-borne diseases such as malaria by simulation analysis of climate models according to various climate scenarios for the next years. Climate variability seems to be determinant for the risk of malaria development (Freeman and Bradley, 1996 [1], Lindsay and Birley, 1996 [2], Kuhn et al., 2005 [3]). Climate can impact on the epidemiology of malaria by several mechanisms, directly, via the development rates and survival of both pathogens and vectors, and indirectly, through changes in vegetation and land surface characteristics such as the variability of breeding sites like ponds.

Scale-up of home-based management of malaria based on rapid diagnostic tests and artemisinin-based combination therapy in a resource-poor country: results in Senegal.

BACKGROUND: Effective case management of malaria requires prompt diagnosis and treatment within 24 hours. Home-based management of malaria (HMM) improves access to treatment for populations with limited access to health facilities. In Senegal, an HMM pilot study in 2008 demonstrated the feasibility of integrated use of RDTs and ACT in remote villages by volunteer Home Care Providers (HCP). Scale-up of the strategy began in 2009, reaching 408 villages in 2009 and 861 villages in 2010. This paper reports the results of the scale-up in the targeted communities and the impact of the strategy on malaria in the formal health sector. METHODS: Data reported by the HCPs were used to assess their performance in 2009 and 2010, while routine malaria morbidity and mortality data were used to assess the impact of the HMM programme. Two high transmission regions where HMM was not implemented until 2010 were used as a comparison. RESULTS AND DISCUSSION: From July 2009 through May 2010, 12582 suspected cases were managed by HCPs, 93% (11672) of whom were tested with an RDT. Among those tested, 37% (4270) had a positive RDT, 97% (4126) of whom were reported treated and cured. Home care providers referred 6871 patients to health posts for management: 6486 with a negative RDT, 119 infants < 2 months, 105 pregnant women, and 161 severe cases. There were no deaths among these patients. In 2009 compared to 2008, incidence of suspected and confirmed malaria cases, all hospitalizations and malaria-related hospitalizations decreased in both intervention and comparison regions. Incidence of in-hospital deaths due to malaria decreased by 62.5% (95% CI 43.8-81.2) in the intervention regions, while the decrease in comparison regions was smaller and not statistically significant. CONCLUSION: Home-based management of malaria including diagnosis with RDT and treatment based on test results is a promising strategy to improve the access of remote populations to prompt and effective management of uncomplicated malaria and to decrease mortality due to malaria. When scaled-up to serve remote village communities in the regions of Senegal with the highest malaria prevalence, home care providers demonstrated excellent adherence to guidelines, potentially contributing to a decrease in hospital deaths attributed to malaria.

Management of uncomplicated malaria in children under 13 years of age at a district hospital in Senegal: from official guidelines to usual practices.

BACKGROUND: To be effective, national malaria guidelines must be properly followed. This study evaluated nurses' practices in the management of uncomplicated malaria cases at a District Hospital. Its objective was to identify the reasons for discrepancies between official guidelines and usual practices. METHODS: This study took place at Oussouye hospital, south-western Senegal. Blood smears were available for biological diagnosis in patients aged more than five years while the Integrated Management of Childhood Illness recommended treating fevers presumptively in children under five. First line anti-malarial was Amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP) bi-therapy. Hospital records of children under 13 years of age seen between 2004 and 2005 were reviewed. RESULTS: Among children treated with anti-malarials, 74% (2, 063/2, 789) received AQ+SP. However, only 22% (406/1, 879) of febrile children and 19% (429/2, 198) of children diagnosed with malaria got a blood smear. Moreover, an anti-malarial was prescribed for 80% (377/474) of children with a negative blood smear. CONCLUSIONS: The transition from chloroquine to AQ+SP was well followed. Nonetheless, blood smear use was very low and many over-prescriptions were reported. Reasons for discrepancies between guidelines and practices can be classified in three main categories: ambiguous guidelines, health system's dysfunctions and nurses' own considerations. Aside from the strengthening of the public health system, in order to guarantee practices complying with guidelines, training content should be more adapted to nurses' own considerations.

Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice.

Previous studies suggested that the cellular prion protein (PrP(c)) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Specifically, amyloid-ß (Aß) oligomers were proposed to cause synaptic and cognitive dysfunction by binding to PrP(c). To test this hypothesis, we crossed human amyloid precursor protein (hAPP) transgenic mice from line J20 onto a PrP(c)-deficient background. Ablation of PrP(c) did not prevent the premature mortality and abnormal neural network activity typically seen in hAPPJ20 mice. Furthermore, hAPPJ20 mice with or without PrP(c) expression showed comparably robust abnormalities in learning and memory and in other behavioral domains at 6-8 months of age. Notably, these abnormalities are not refractory to therapeutic manipulations in general: they can be effectively prevented by interventions that prevent Aß-dependent neuronal dysfunction also in other lines of hAPP transgenic mice. Thus, at least in this model, PrP(c) is not an important mediator of Aß-induced neurological impairments.

The extracellular regulated kinase-1 (ERK1) controls regulated alpha-secretase-mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein.

The α-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrP(c)) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrP(c) processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant-negative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrP(c). We demonstrate that the ERK1-associated increase in PrP(c) promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrP(c) cellular homeostasis and indicate that this kinase exerts a dual control of PrP(c) levels through transcriptional and post-transcriptional mechanisms.