Ballistic electron transport through magnetic domain walls

Electron transport limited by the rotating exchange-potential of domain walls is calculated in the ballistic limit for the itinerant ferromagnets Fe, Co, and Ni. When realistic band structures are used, the domain wall magnetoresistance is enhanced by orders of magnitude compared to the results for previously studied two-band models. Increasing the pitch of a domain wall by confinement in a nano-structured point contact is predicted to give rise to a strongly enhanced magnetoresistance.Comment: 4 pages, 2 figures; to appear in PRB as a brief repor

Is kallikrein-8 a blood biomarker for detecting amnestic mild cognitive impairment? Results of the population-based Heinz Nixdorf Recall study

Background!#!Kallikrein-8 (KLK8) might be an early blood-biomarker of Alzheimer's disease (AD). We examined whether blood KLK8 is elevated in persons with amnestic mild cognitive impairment (aMCI) which is a precursor of AD, compared to cognitively unimpaired (CU) controls.!##!Methods!#!Forty cases and 80 controls, matched by sex and age (± 3years), were participants of the longitudinal population-based Heinz Nixdorf Recall study (baseline: 2000-2003). Standardized cognitive performance was assessed 5 (T1) and 10 years after baseline (T2). Cases were CU at T1 and had incidental aMCI at T2. Controls were CU at T1 and T2. Blood KLK8 was measured at T2. Using multiple logistic regression the association between KLK8 in cases vs. controls was investigated by estimating odds ratios (OR) and 95% confidence intervals (95%CI), adjusted for inter-assay variability and freezing duration. Using receiver operating characteristic (ROC) analysis, the diagnostic accuracy of KLK8 was determined by estimating the area under the curve (AUC) and 95%CI (adjusted for inter-assay variability, freezing duration, age, sex).!##!Results!#!Thirty-seven participants with aMCI vs. 72 CU (36.7%women, 71.0±8.0 (mean±SD) years) had valid KLK8 measurements. Mean KLK8 was higher in cases than in controls (911.6±619.8 pg/ml vs.783.1±633.0 pg/ml). Fully adjusted, a KLK8 increase of 500pg/ml was associated with a 2.68 (1.05-6.84) higher chance of having aMCI compared to being CU. With an AUC of 0.92 (0.86-0.97), blood KLK8 was a strong discriminator for aMCI and CU.!##!Conclusion!#!This is the first population-based study to demonstrate the potential clinical utility of blood KLK8 as a biomarker for incipient AD

The interaction of insoluble Amyloid‐β with soluble Amyloid‐β dimers decreases Amyloid‐β plaque numbers

ObjectivesThe heterogeneity of Amyloid‐beta (Aβ) plaque load in patients with Alzheimer's disease (AD) has puzzled neuropathology. Since brain Aβ plaque load does not correlate with cognitive decline, neurotoxic soluble Aβ oligomers have been championed as disease‐causing agents in early AD. So far, investigating molecular interactions between soluble oligomeric Aβ and insoluble Aβ in vivo has been difficult because of the abundance of Aβ oligomer species and the kinetic equilibrium in which they coexist. Here, we investigated whether Aβ plaque heterogeneity relates to interactions of different Aβ conformers.Materials and MethodsWe took advantage of transgenic mice that generate exclusively Aβ dimers (tgDimer mice) but do not develop Aβ plaques or neuroinflammation during their lifetime, crossed them to the transgenic CRND8 mice that develop plaques after 90 days and measured Aβ plaque load using immunohistochemical and biochemical assays. Furthermore, we performed in vitro thioflavin T (ThT) aggregation assays titrating synthetic Aβ42‐S8C dimers into fibril‐forming synthetic Aβ42.ResultsWe observed a lower number of Aβ plaques in the brain of double transgenic mice compared to tgCRND8 mice alone while the average plaque size remained unaltered. Corroborating these in vivo findings, synthetic Aβ‐S8C dimers inhibited fibril formation of wild‐type Aβ also in vitro, seen by an increased half‐time in the ThT assay.ConclusionsOur study indicates that Aβ dimers directly interfere with Aβ fibril formation in vivo and in vitro. The variable interaction of Aβ dimers with insoluble Aβ seeds could thus contribute to the heterogeneity of Aβ plaque load in AD patients

Acute systemic rapamycin induces neurobehavioral alterations in rats

Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning

The Multi-target Effects of CNI-1493: Convergence of Antiamylodogenic and Antiinflammatory Properties in Animal Models of Alzheimer’s Disease

Abstract After several decades of Alzheimer’s disease (AD) research and failed clinical trials, one can speculate that targeting a single pathway is not sufficient. However, a cocktail of novel therapeutics will constitute a challenging clinical trial. A more plausible approach will capitalize on a drug that has relevant and synergistic multiple-target effects in AD. We have previously demonstrated the efficacy of CNI-1493 in the CRND8 transgenic AD mouse model. Similar to many antiinflammatory drugs that were tested in preclinical models of AD, it was speculated that the significant effect of CNI-1493 is due to its established antiinflammatory properties in rodents and humans. In the present study, we set out to elucidate the protective mechanism of CNI-1493 as a drug simultaneously targeting several aspects of AD pathology. Using C1213, a highly similar analogue of CNI-1493 that lacks antiinflammatory properties, we show that both compounds directly interact with soluble and insoluble amyloid β (Aβ) aggregates and attenuate Aβ cytotoxicity in vitro. Additionally, CNI-1493 and C1213 ameliorates Aβ-induced behavioral deficits in nematodes. Finally, C1213 reduces Aβ plaque burden and cognitive deficits in transgenic CRND8 mice to a similar extent as previously shown with CNI-1493. Taken together, our findings suggest antiamyloidogenic activity as a relevant component of the in vivo efficacy of CNI-1493 and its analogue C1213. Thus, CNI-1493, a drug with proven safety in humans, is a viable candidate for novel multitarget therapeutic approaches to AD

Compromised Hippocampal Neuroplasticity in the Interferon-alpha and Toll-like Receptor-3 Activation-Induced Mouse Depression Model

Disrupted neuronal plasticity due to subtle inflammation is considered to play a fundamental role in the pathogenesis of major depressive disorder. Interferon-alpha (IFN-alpha) potentiates immune responses against viral pathogens that induce toll-like receptor-3 (TLR3) activation but evokes severe major depressive disorder in humans by mechanisms that remain insufficiently described. By using a previously established mouse model of depression induced by combined delivery of IFN-alpha and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, we provide evidence that IFN-alpha and poly(I:C) reduce apical dendritic spine density in the hippocampal CA1 area ex vivo via mechanisms involving decreased TrkB signaling. In vitro, IFN-alpha and poly(I:C) treatments required neuronal activity to reduce dendritic spine density and TrkB signaling. The levels of presynaptic protein vesicular glutamate transporter (VGLUT)-1 and postsynaptic protein postsynaptic density-95 (PSD95) were specifically decreased, whereas the expression of both synaptic and extrasynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPAR1) was increased by IFN-alpha and poly(I:C) delivery. Patch clamp recordings in primary hippocampal neurons revealed that morphological changes at the synapse induced by IFN-alpha and poly(I:C) costimulation were accompanied by an increased action potential threshold and action potential frequency, indicative of impaired neuronal excitability. Taken together, IFN-alpha and poly(I:C) delivery leads to structural and functional alterations at the synapse indicating that compromised neuroplasticity may play an integral role in the pathogenesis of immune response-induced depression

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice : Involvement of Multiple Pathways

Diversity and intensity of intellectual and physical activities seem to have an inverse relationship with the extent of cognitive decline in Alzheimer’s disease (AD). To study the interaction between an active lifestyle and AD pathology, female TgCRND8 mice carrying human APPswe+ind were transferred into enriched housing. Four months of continuous and diversified environmental stimulation resulted in a significant reduction of β-amyloid (Aβ) plaques and in a lower extent of amyloid angiopathy. Neither human amyloid precursor protein (APP) mRNA/protein levels nor the level of carboxy-terminal fragments of APP nor soluble Aβ content differed between both groups, making alterations in APP expression or processing unlikely as a cause of reduced Aβ deposition. Moreover, DNA microarray analysis revealed simultaneous down-regulation of proinflammatory genes as well as up-regulation of molecules involved in anti-inflammatory processes, proteasomal degradation, and cholesterol binding, possibly explaining reduced Aβ burden by lower aggregation and enhanced clearance of Aβ. Additionally, immunoblotting against F4/80 antigen and morphometric analysis of microglia (Mac-3) revealed significantly elevated microgliosis in the enriched brains, which suggests increased amyloid phagocytosis. In summary, this study demonstrates that the environment interacts with AD pathology at dif-ferent levels