Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer's disease transgenic mice: an insight into the pathogenic effects of amyloid-β

The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-β (Aβ) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between Aβ levels and VDAC1 expression. In hippocampal extracts from transgenic mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3β, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD

Nuclear Photoabsorption at Photon Energies between 300 and 850 Mev

We construct the formula for the photonuclear total absorption cross section using the projection method and the unitarity relation. Our treatment is very effective when interference effects in the absorption processes on a nucleon are strong. The disappearance of the peak around the position of the $D_{13}$ resonance in the nuclear photoabsorption can be explained with the cooperative effect of the interference in two-pion production processes,the Fermi motion, the collision broadenings of $\Delta$ and $N^*$, and the pion distortion in the nuclear medium. The change of the interference effect by the medium plays an important role.Comment: 22pages,7figures,revtex

Overexpression of wild-type human APP in mice causes cognitive déficits and pathological features unrelated to Abeta levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ- independent pathogenic pathways in Alzheimer's disease

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer’s Disease

Abstract. Synapse loss occurs early in Alzheimer’s disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPPswe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPPswe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD

Rosiglitazone Rescues Memory Impairment in Alzheimer's Transgenic Mice: Mechanisms Involving a Reduced Amyloid and Tau Pathology

Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARγ) may exert beneficial effects in patients with mild-to-moderate Alzheimer's disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARγ, facilitated β-amyloid peptide (Aβ) clearance. Rosiglitazone not only reduced Aβ burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients

Hysteretic giant magnetoimpedance effect analyzed by first-order reversal curves

Hysteretic giant magnetoimpedance (GMI) of amorphous ribbons with a well-defined transversal domain structure is investigated by means of first-order reversal curves (FORC) analysis. The FORCs are not confined to the hysteretic area, exceeding the major curve amplitude. Irreversible switches of the transverse permeability, caused by domain wall structure transitions, may be the origin of the observed FORC distribution. An interlinked hysteron/anti-hysteron model is proposed to interpret it, which allows analyzing the influence of frequency and magnetostriction upon the hysteretic GMI effect.Comment: 19 pages, 9 figure

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Hypercoagulability and ischemic stroke in young patients

Introduction: Hypercoagulable states have been reported as an established risk factor for cerebral venous thrombosis, but they have also been proposed as a predisposing factor for cerebral ischemia of arterial origin, especially among young patients. This may have implications on therapeutic management and secondary prevention. We have studied the frequency of prothrombotic abnormalities in young patients with ischaemic stroke, as other classic risk factors are less common in this group. Materials and methods: Observational study with sequential inclusion of patients under 55 with stroke or transient ischaemic attack (TIA) admitted to the Stroke Unit from January 2005 through December 2007. We analysed demographic data, severity and subtype of stroke, risk factors, including the presence of hypercoagulable states, and outcome. Results: We included 100 patients, of whom 65 were men. The mean age was 42.6 ± 8.9 years, 46% with a hypercoagulable state, and no sex differences. Acquired hyperhomocysteinemia was the most common abnormality (18%), followed by protein C or S deficiency (8%), factor V Leiden mutation (5%) and methylenetetrahydrofolate reductase (MTHFR) C677T mutation (5%). Other findings included anticardiolipin antibodies (3%), presence of lupus anticoagulant (2%), thrombocytosis (3%) and G20210A prothrombin gene mutation (3%). No association was found between these states and the presence of other vascular risk factors, or more severe stroke or worse outcomes. There was an increased presence of these abnormalities in patients who were classified as atherothrombotic stroke (p = 0.04). Conclusions: The hypercoagulable states are common in young patients with ischaemic stroke, being present in up to 46% of them. Resumen: Introducción: Los estados de hipercoagulabilidad se han estudiado como una de las posibles etiologías de la trombosis venosa cerebral y, desde hace unos años, también como factor predisponente de isquemia cerebral de origen arterial, especialmente en pacientes jóvenes. Esto podría tener implicaciones en el manejo terapéutico y la prevención secundaria, por lo que nos proponemos estudiar la frecuencia de anomalías protrombóticas en pacientes jóvenes con ictus isquémico, subgrupo en que otros factores de riesgo clásicos son menos habituales. Material y métodos: Estudio observacional con inclusión secuencial de los pacientes menores de 55 años con infarto cerebral o ataque isquémico transitorio ingresados en la unidad de ictus desde enero de 2005 hasta diciembre de 2007. Se analizaron datos demográficos, gravedad y subtipo de ictus, factores de riesgo, incluidos los estados de hipercoagulabilidad, y evolución. Resultados: Se incluyó a 100 pacientes, de los que 65 eran varones, con una media ± desviación estándar de edad de 42,6 ± 8,9 años. El 46% presentó estado de hipercoagulabilidad, sin diferencia por sexo. La hiperhomocisteinemia adquirida fue la alteración más frecuente (18%), seguida del déficit de proteína C o S (8%), la mutación para el factor V de Leiden (5%) y la mutación C677T del gen de la metiltetrahidrofolato reductasa (MTHFR) (5%). Otras alteraciones procoagulantes fueron síndrome antifosfolípido (3%), anticoagulante lúpico (2%), trombocitosis (3%) y mutación 20210A del gen de la protrombina (3%). No se encontró relación de estas alteraciones con otros factores de riesgo vascular, como tampoco se relacionó la hipercoagulabilidad con el ictus de mayor gravedad o peor evolución. Se observó una mayor presencia de estas alteraciones en los pacientes catalogados de ictus de origen aterotrombótico (p = 0,04). Conclusiones: Los estados de hipercoagulabilidad son frecuentes en los pacientes menores de 55 años con ictus isquémico, encontrándose hasta en el 46% de ellos. Keywords: Hypercoagulability, Stroke, Cryptogenic stroke, Palabras clave: Hipercoagulabilidad, Infarto cerebral, Infarto cerebral criptogénic

Previous statins treatment and risk of post-stroke infections

Introduction: Clinical and laboratory studies have attributed an inmuno-supressor effect to the statins. Furthermore, the administration of simvastatin in the acute onset of stroke has been associated with an increased infection frequency. Our objective is to assess the influence of statins previous treatment on infection after ischemic stroke. Patients and methods: Observational study of patients with ischaemic stroke hospitalised in a Stroke Unit. Demographic data, vascular risk factors, stroke severity, stroke subtype and previous statins treatment were evaluated. The following infections were registered: pneumonia, urinary tract infection, pseudomembranous colitis and sepsis. The patients were classified into two groups, depending on previous statin treatment. Results: A total of 2045 patients were included (1165 were male, aged 69.05 ± 12.5 years). Of these, 306 (15%) patients were receiving statins prior to stroke. These patients had more frequently arterial hypertension, DM, peripheral arterial disease and hypercholesterolaemia than the patients who were not treated with statins (P < 0001). There was no statistically significant difference between overall in-hospital infection frequency between patients treated with statins and those with no statins treatment, (11.8% vs. 13%), nor in individual infection type: pneumonia (7.8% vs. 10.2%), urinary tract infection (4.2% vs. 2.8%), pseudomembranous colitis (0.3% vs. 0.7%) and sepsis (2.6% vs. 4.4%). In the atherothrombotic stroke subtype, statins were associated with a lower frequency of sepsis (unadjusted OR, 0.949; 95% CI; 0.928–0.971). Conclusions: Previous treatment with statins does not appear to infl uence the frequency of in-hospital infections in patients with ischaemic stroke. Resumen: Introducción y objetivo: Diversos estudios clínicos y experimentales atribuyen un efecto inmunosupresor a las estatinas y la administración de simvastatina en la fase aguda del ictus se ha asociado a mayor frecuencia de infecciones durante el ingreso. Nuestro objetivo es comprobar si el consumo previo de estatinas infl uye en la aparición de complicaciones infecciosas intrahospitalarias tras un infarto cerebral (IC). Pacientes y métodos: Estudio observacional incluyendo pacientes con IC ingresados en la Unidad de Ictus. Se analizan: datos demográficos, factores de riesgo vascular, gravedad al ingreso, subtipo etiológico de infarto cerebral y consumo previo de estatinas. Se ha estudiado la aparición de las siguientes complicaciones infecciosas durante la hospitalización: neumonía, infección urinaria, colitis pseudomembranosa y sepsis de cualquier origen agrupando a los enfermos en dos grupos: pacientes que previamente tomaban o no estatinas. Resultados: Se incluyeron 2.045 pacientes (1.162 varones) con edad media de 69,05 años (DE 12,5). El 15% (306 pacientes) tomaba estatinas previamente al IC. Dichos pacientes presentaban con mayor frecuencia que los que no lo hacían (p < 0,0001) antecedente de HTA, DM, arteriopatía periférica e hipercolesterolemia. La frecuencia de infección intrahospitalaria fue similar en ambos grupos, tanto evaluada de manera global (11,8% vs 13%, p = 0,643) como al analizar cada una de las infecciones separadamente. En el subgrupo de IC aterotrombótico, las estatinas se asociaron con una menor frecuencia de sepsis (OR no ajustado 0,949, IC 95% [0,928–0,971]). Conclusiones: El tratamiento previo con estatinas parece no influir en la frecuencia de complicaciones infecciosas intrahospitalarias tras un IC agudo. Keywords: Stroke, Statins, Complications, Infections, : lctus, Estatinas, Complicaciones, Infeccione