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<i>In vivo</i> imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model
摘要： Pathological alterations of tau protein play a significant role in the emergence and progression of neurodegenerative disorders. Tauopathies are characterized by detachment of the tau protein from neuronal microtubules, and its subsequent aberrant hyper-phosphorylation, aggregation and cellular distribution. The exact nature of tau protein species causing neuronal malfunction and degeneration is still unknown. In the present study, we used mice transgenic for human tau with the frontotemporal dementia with parkinsonism-associated P301S mutation. These mice are prone to develop fibrillar tau inclusions, especially in the spinal cord and brainstem. At the same time, cortical neurons are not as strongly affected by fibrillar tau forms, but rather by soluble tau forms. We took advantage of the possibility to induce formation of neurofibrillary tangles in a subset of these cortical neurons by local injection of preformed synthetic tau fibrils. By using chronic in vivo two-photon calcium imaging in awake mice, we were able for the first time to follow the activity of individual tangle-bearing neurons and compare it to the activity of tangle-free neurons over the disease course. Our results revealed strong reduction of calcium transient frequency in layer 2/3 cortical neurons of P301S mice, independent of neurofibrillary tangle presence. These results clearly point to the impairing role of soluble, mutated tau protein species present in the majority of the neurons investigated in this study.
关键词： neurofibrillary tangles,two-photon imaging,tau,seeding,P301S mice
更新于2025-11-21 11:08:12
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PET-Liganden für die Diagnostik der Alzheimer-Demenz: Amyloid und Tau
摘要： Over the last 15 years diagnostic imaging of amyloid and tau deposits with PET has gained increasing importance especially in the context of diagnosis of dementia such as Alzheimer's disease. First radiotracers that were developed aimed at the detection of amyloid plaques in the brain. In the meantime the contribution of hyperphosphorylated proteins (TAU) that lead to another type of protein deposits is getting more and more in the focus of current research on the origin of this disease. While a number of 18F-labelled ligands for amyloid imaging have recently been granted marketing authorization and therefore are commercially available and can be used by licensed nuclear medicine physicians throughout Europe and the US, this is not true for radiotracers for TAU-protein imaging. Therefore their use is restricted to clinical trials or to the application of in house manufactured substances. This article should give an overview on characteristics, development and availability of PET tracers for amyloid and tau imaging and in addition to that exemplify the challenges associated with a GMP compliant manufacturing of these short lived radiotracers.
关键词： Alzheimer,18F,Amyloid,11C,PET,Tau
更新于2025-09-23 15:22:29
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A UV cross-linking method combined with infrared imaging to analyse RNA–protein interactions
摘要： Photo cross-linking of proteins with short RNA oligomers is a classical method to study RNA–protein interactions that are implicated in many aspects of RNA metabolism and function. Most commonly, this involves the use of [c-32P]-labeled RNA probes. Although very sensitive, these procedures are complicated by the safety issues associated with the use of radioisotopes. Here, we describe a modi?ed UV cross-linking method using oligonucleotide probes end labelled with the infrared dye IRDyeVR 800. After UV cross-linking, proteins are separated by SDS-PAGE and cross-linked products are visualized with the OdysseyVR Infrared Imaging system. This end labelling approach provides a streamlined alternative to random labelling which reduces the ef?ciency of in-vitro transcription. End labelling is also independent of the length of the probe, thus facili- tating quantitative comparisons. To validate the method, we have con?rmed the binding of HuD to the 30-UTR of the mRNA for the microtubule-associated protein tau, implicated in the pathogenesis of Alzheimer’s disease. UV cross-linking of HuD with a labeled 21-mer probe was successfully performed using a recombinant puri?ed glutathione-S-transferase–HuD fu- sion protein as well as with lysates from CHO cells transfected with HuD cDNA. UV cross-linking combined with infrared imaging offers a convenient and robust strategy to analyse RNA–protein interactions and their emerging importance in disease.
关键词： Tau,RNA-binding protein,UV cross-linking,neurodegeneration,HuD,OdysseyVR
更新于2025-09-23 15:19:57
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Microtubule network as a potential candidate for targeting by gold nanoparticle-assisted photothermal therapy
摘要： Photothermal therapy is achieving ever-increasing attention as a promising method for killing cancer cells. Although, gold nanoparticles are regarded as one of the most effective photothermal therapy agents, the mechanisms underlying their action have to be addressed. Moreover, studies have showed that gold nanoparticles induce apoptosis in treated cultures. Hence, in this study, we investigated the interaction of folic acid functionalized gold nanoparticles and gold-shelled Fe3O4 nanoparticles with microtubule and microtubule associated protein tau in order to introduce intracellular targets of these nanoparticles and provide a holistic view about the mechanism of action of gold nanoparticles used in photothermal therapy. Various spectroscopic methods were used to find gold nanoparticles interaction with Tubulin and Tau. Our results indicated that these gold nanoparticles interact with both Tau and Tubulin and their affinity increases as temperature rises. Also, the results illustrated that quenching mechanism for gold nanoparticles interaction with Tubulin and Tau was static. The hydrophobic interaction was determined as driving force for gold nanoparticles binding to Tubulin and Tau. Moreover, it was showed that both type of gold nanoparticles stabilize microtubule polymers. These results suggest Tau and Tubulin as intracellular target of gold nanoparticles and propose that microtubule network is at the heart of apoptosis mechanisms initiated by photothermal therapy.
关键词： Gold-shelled Fe3O4 nanoparticles,Tubulin,Gold nanoparticles,Tau protein,Photothermal therapy
更新于2025-09-19 17:15:36
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Femtomolar sensing of Alzheimer's tau proteins by water oxidation-coupled photoelectrochemical platform
摘要： Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. A key pathogenic event of AD is the formation of intracellular neurofibrillary tangles that are mainly composed of tau proteins. Here, we report on ultrasensitive detection of total tau (t-tau) proteins using an artificial electron donor-free, BiVO4-based photoelectrochemical (PEC) analysis. The platform was constructed by incorporating molybdenum (Mo) dopant and iron oxyhydroxide (FeOOH) ad-layer into the BiVO4 photoelectrode and employing a signal amplifier formed by horseradish peroxidase (HRP)-triggered oxidation of 3,3′-diaminobenzidine (DAB). Despite the absence of additional electron suppliers, the FeOOH/Mo:BiVO4 conjugated with the Tau5 antibody produced strong current signals at 0 V (vs. Ag/AgCl, 3M NaCl) under the illumination of a white light-emitting diode. The Mo extrinsic dopants increased the charge carrier density of BiVO4-Tau5 by 1.57 times, and the FeOOH co-catalyst promoted the interfacial water oxidation reaction of Mo:BiVO4-Tau5 by suppressing charge recombination. The introduction of HRP-labeled Tau46 capture antibodies to the FeOOH/Mo:BiVO4-Tau5 platform produced insoluble precipitation on the transducer by accelerating the oxidation of DAB, which amplified the photocurrent signal of FeOOH/Mo:BiVO4-Tau5 by 2.07-fold. Consequently, the water oxidation-coupled, FeOOH/Mo:BiVO4-based PEC sensing platform accurately and selectively recognized t-tau proteins down to femtomolar concentrations; the limit of detection and limit of quantification were determined to be 1.59 fM and 4.11 fM, respectively.
关键词： Alzheimer’s disease,water oxidation,Femtomolar sensitivity,tau proteins,BiVO4
更新于2025-09-19 17:13:59
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Tau <scp>PET</scp> Imaging for Staging of Alzheimer's Disease in Down Syndrome
摘要： Alzheimer’s disease (AD) pathology and early-onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology. Recent work indicates that amyloid pathology develops 15-20 years before neurodegeneration and symptom onset in the sporadic and autosomal dominant forms of AD, while tau pathology correlates more closely with symptomatic stages evidenced by cognitive decline and dementia. Recent work on AD biomarkers in DS illustrates similarities between DS and sporadic AD. It may soon be possible to apply recently developed staging classifications to DS to obtain a more nuanced understanding of the development AD in DS and to provide a more accurate diagnosis and prognosis in the clinic.
关键词： Tau PET,Down syndrome,Alzheimer’s disease
更新于2025-09-04 15:30:14
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Diagnostic of stellar magnetic fields with cumulative circular polarisation profiles
摘要： Information about stellar magnetic ?eld topologies is obtained primarily from high-resolution circular polarisation (Stokes V) obser- vations. Because of their generally complex morphologies, the stellar Stokes V pro?les are usually interpreted with elaborate inversion techniques such as Zeeman Doppler imaging (ZDI). Here we further develop a new method for interpreting circular polarisation sig- natures in spectral lines using cumulative Stokes V pro?les (anti-derivative of Stokes V). This method is complimentary to ZDI and can be applied to validate the inversion results or when the available observational data are insu?cient for an inversion. Based on the rigorous treatment of polarised line formation in the weak-?eld regime, we show that, for rapidly rotating stars, the cumulative Stokes V pro?les contain information about the spatially resolved longitudinal magnetic ?eld density. Rotational modulation of these pro?les can be employed for a simple, qualitative characterisation of the stellar magnetic ?eld topologies. We apply this diagnostic method to the archival observations of the weak-line T Tauri star V410 Tau and Bp He-strong star HD 37776. We show that the magnetic ?eld in V410 Tau is dominated by an azimuthal component, in agreement with the ZDI map that we recover from the same data set. For HD 37776 the cumulative Stokes V pro?le variation indicates the presence of multiple regions of positive and negative ?eld polarity. This behaviour agrees with the ZDI results, but contradicts the popular hypothesis that the magnetic ?eld of this star is dominated by an axisymmetric quadrupolar component.
关键词： stars: individual: HD 37776,stars: magnetic ?eld,stars: individual: V410 Tau,magnetic ?elds,stars: activity
更新于2025-09-04 15:30:14