In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
Background and purpose
Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between ...infectious burden (IB) and Alzheimer's disease (AD) was examined.
Methods
Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.
Results
Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.
Conclusions
IB consisting of CMV, HSV‐1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
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This paper is concerned with the polynomial filtering problem for a class of nonlinear systems with quantisations and missing measurements. The nonlinear functions are approximated with polynomials ...of a chosen degree and the approximation errors are described as low-order polynomial terms with norm-bounded coefficients. The transmitted outputs are quantised by a logarithmic quantiser and are also subject to randomly missing measurements governed by a Bernoulli distributed sequence taking values on 0 or 1. Dedicated efforts are made to derive an upper bound of the filtering error covariance in the simultaneous presence of the polynomial approximation errors, the quantisations as well as the missing measurements at each time instant. Such an upper bound is then minimised through designing a suitable filter gain by solving a set of matrix equations. The filter design algorithm is recursive and therefore applicable for online computation. An illustrative example is exploited to show the effectiveness of the proposed algorithm.
The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. ...However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.
Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques ...consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.
Abstract
Magnetization plateaus in quantum magnets—where bosonic quasiparticles crystallize into emergent spin superlattices—are spectacular yet simple examples of collective quantum phenomena ...escaping classical description. While magnetization plateaus have been observed in a number of spin-1/2 antiferromagnets, the description of their magnetic excitations remains an open theoretical and experimental challenge. Here, we investigate the dynamical properties of the triangular-lattice spin-1/2 antiferromagnet Ba
3
CoSb
2
O
9
in its one-third magnetization plateau phase using a combination of nonlinear spin-wave theory and neutron scattering measurements. The agreement between our theoretical treatment and the experimental data demonstrates that magnons behave semiclassically in the plateau in spite of the purely quantum origin of the underlying magnetic structure. This allows for a quantitative determination of Ba
3
CoSb
2
O
9
exchange parameters. We discuss the implication of our results to the deviations from semiclassical behavior observed in zero-field spin dynamics of the same material and conclude they must have an intrinsic origin.
Graphene has shown great application potential as the host material for next-generation electronic devices. However, despite its intriguing properties, one of the biggest hurdles for graphene to be ...useful as an electronic material is the lack of an energy gap in its electronic spectra. This, for example, prevents the use of graphene in making transistors. Although several proposals have been made to open a gap in graphene's electronic spectra, they all require complex engineering of the graphene layer. Here, we show that when graphene is epitaxially grown on SiC substrate, a gap of approximately 0.26 eV is produced. This gap decreases as the sample thickness increases and eventually approaches zero when the number of layers exceeds four. We propose that the origin of this gap is the breaking of sublattice symmetry owing to the graphene-substrate interaction. We believe that our results highlight a promising direction for bandgap engineering of graphene.
This paper is concerned with the distributed state estimation problem over wireless sensor networks. The communication links are unreliable that are subject to random link failures modeled as a set ...of independent Bernoulli processes. To estimate the plant state collaboratively, a Kalman-consensus filtering approach is developed where the sensors spread the local information obtained from the Kalman filtering algorithm by performing a consensus of the inverse covariance matrices at each time instant. Sufficient conditions for the stochastic boundedness of the Kalman-consensus filter are established. It is shown that the filtering performance is directly influenced by the network connectivity and the collective observability. A numerical example is illustrated to verify the proposed results.
In conventional superconductors, the electron pairing that allows superconductivity is caused by exchange of virtual phonons, which are quanta of lattice vibration. For high-transition-temperature ...(high-Tc) superconductors, it is far from clear that phonons are involved in the pairing at all. For example, the negligible change in Tc of optimally doped Bi2Sr2CaCu2O8+δ (Bi2212; ref. 1) upon oxygen isotope substitution (16O → 18O leads to Tc decreasing from 92 to 91 K) has often been taken to mean that phonons play an insignificant role in this material. Here we provide a detailed comparison of the electron dynamics of Bi2212 samples containing different oxygen isotopes, using angle-resolved photoemission spectroscopy. Our data show definite and strong isotope effects. Surprisingly, the effects mainly appear in broad high-energy humps, commonly referred to as 'incoherent peaks'. As a function of temperature and electron momentum, the magnitude of the isotope effect closely correlates with the superconducting gap-that is, the pair binding energy. We suggest that these results can be explained in a dynamic spin-Peierls picture, where the singlet pairing of electrons and the electron-lattice coupling mutually enhance each other.
Originating from relativistic quantum field theory, Dirac fermions have been invoked recently to explain various peculiar phenomena in condensed-matter physics, including the novel quantum Hall ...effect in graphene, the magnetic-field-driven metal-insulator-like transition in graphite, superfluidity in 3He (ref. 5) and the exotic pseudogap phase of high-temperature superconductors. Despite their proposed key role in those systems, direct experimental evidence of Dirac fermions has been limited. Here, we report the first direct observation of relativistic Dirac fermions with linear dispersion near the Brillouin zone (BZ) corner H, which coexist with quasiparticles that have a parabolic dispersion near another BZ corner K. In addition, we also report a large electron pocket that we attribute to defect-induced localized states. Thus, graphite presents a system in which massless Dirac fermions, quasiparticles with finite effective mass and defect states all contribute to the low-energy electronic dynamics.
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