Search Results (22)

In Alzheimer’s disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S proteasome, macroautophagy, and aggrephagy. Neurofibrillary tangles (NFTs) form upon the impairment of aggrephagy, and eventually, the ubiquitin chaperone valosin-containing protein (VCP) and heat shock 70 kDa protein (HSP70) are recruited to the sites of NFTs for the extraction of tau for the ubiquitin–proteasome system (UPS)-mediated degradation. However, the impairment of tau degradation in neurons allows tau to be secreted into the extracellular space. Secreted tau can be monomers, oligomers, and paired helical filaments (PHFs), which are seeding competent pathological tau that can be endocytosed/phagocytosed by healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes, often causing proteotoxic stress and eventually triggers senescence. Senescent cells secrete various senescence-associated secretory phenotype (SASP) factors, which trigger cellular atrophy, causing decreased brain volume in human AD. However, the molecular mechanisms of proteotoxic stress and cellular senescence are not entirely understood and are an emerging area of research. Therefore, this comprehensive review summarizes pertinent studies that provided evidence for the sequential tau degradation, failure, and the mechanistic link between tau-driven proteotoxic stress and cellular senescence in AD. Full article

Multipulse laser–matter interactions initiate nonlinear and nonequilibrium plasma fluid flow dynamics and their instability creating microscale vortex filaments, loop-soliton chains, and helically paired structures, similar to those at the astrophysical mega scale. We show that the equation with the Hasimoto structure describes both, the creation of loop solitons by torsion of vortex filaments and the creation of solitons by helical winding of magnetic field lines in the Crab Nebula. Our experiments demonstrate that the breakup of the loop solitons creates vortex rings with (i) quasistatic toroidal Kelvin waves and (ii) parametric oscillatory modes—i.e., with the hierarchical instability order. For the first time, we show that the same hierarchical instability at the micro- and the megascale establishes the conceptual frame for their unique classification based on the hierarchical order of Bessel functions. Present findings reveal that conditions created in the laser-target regions of a high filament density lead to their collective behavior and formation of helically paired and filament-braided “complexes”. We also show, for the first time, that morphological and topological characteristics of the filament-bundle “complexes” with the loop solitons indicate the analogy between similar laser-induced plasma instabilities and those of the Crab and Double-Helix Nebulas—thus enabling conceptualization of fundamental characteristics. These results reveal that the same rotating metric accommodates the complexity of the instabilities of helical filaments, vortex rings, and filament jets in the plasmatic micro- and megascale astrophysical objects. Full article

Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer’s disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer’s disease. Brain ischemia and Alzheimer’s disease are two diseases characterized by similar changes in the hippocampus that are closely related to memory impairment. Following brain ischemia in animals and humans, the presence of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles was revealed. The phenomenon of tau protein hyperphosphorylation is a similar pathological feature of both post-ischemic brain injury and Alzheimer’s disease. In Alzheimer’s disease, the phosphorylated Thr231 motif in tau protein has two distinct trans and cis conformations and is the primary site of tau protein phosphorylation in the pre-entanglement cascade and acts as an early precursor of tau protein neuropathology in the form of neurofibrillary tangles. Based on the latest publication, we present a similar mechanism of the formation of neurofibrillary tangles after brain ischemia as in Alzheimer’s disease, established on trans- and cis-phosphorylation of tau protein, which ultimately influences the development of tauopathy. Full article

Natively unfolded tau has a low propensity to form aggregates, but in tauopathies, such as Alzheimer’s disease (AD), tau aggregates into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Multiple intracellular transport pathways utilize kinesin-1, a plus-end-directed microtubule-based motor. Kinesin-1 is crucial in various neurodegenerative diseases as it transports multiple cargoes along the microtubules (MT). Kinesin-1 proteins cannot progress along MTs due to an accumulation of tau on their surfaces. Although kinesin-1-mediated neuronal transport dysfunction is well-documented in other neurodegenerative diseases, its role in AD has received less attention. Very recently, we have shown that knocking down and knocking out of kinesin-1 heavy chain (KIF5B KO) expression significantly reduced the level and stability of tau in cells and tau transgenic mice, respectively. Here, we report that tau interacts with the motor domain of KIF5B in vivo and in vitro, possibly through its microtubule-binding repeat domain. This interaction leads to the inhibition of the ATPase activity of the motor domain. In addition, the KIF5B KO results in autophagy initiation, which subsequently assists in tau degradation. The mechanisms behind KIF5B KO-mediated tau degradation seem to involve its interaction with tau, promoting the trafficking of tau through retrograde transport into autophagosomes for subsequent lysosomal degradation of tau. Our results suggest how KIF5B removal facilitates the movement of autophagosomes toward lysosomes for efficient tau degradation. This mechanism can be enabled through the downregulation of kinesin-1 or the disruption of the association between kinesin-1 and tau, particularly in cases when neurons perceive disturbances in intercellular axonal transport. Full article

Background: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models. Methods: We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms. The spatiotemporal development of tau pathology was investigated immunohistochemically. Levels of sarkosyl-insoluble paired helical filaments were determined via a MesoScale Discovery biomarker assay. Results: Neuromotor impairments developed from age 3 months in both models. On electron microscopy, spinal cord neurofibrillary pathology was visible in mice aged 3 months; however, AT8 immunoreactivity was not yet observed in Tau58/4 mice. Behavioral abnormalities and memory deficits occurred at a later stage (>9 months) when tau pathology was fully disseminated throughout the brain. Spatiotemporally, tau pathology spread from the spinal cord via the midbrain to the frontal cortex, while the hippocampus was relatively spared, thus explaining the late onset of cognitive deficits. Conclusions: Our findings indicate the face and construct validity of both Tau58 models, which may provide new, valuable insights into the pathologic effects of tau species in vivo and may consequently facilitate the development of new therapeutic targets to delay or halt neurodegenerative processes occurring in tauopathies. Full article

Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer’s disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[¹²⁵I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([¹²⁵I]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [¹²⁵I]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically. Computational modeling of INFT binding on Tau fibril was compared with IPPI. In vitro, autoradiography studies were conducted with [¹²⁵I]INFT for Tau in AD and cognitively normal (CN) brains. [¹²⁵I]INFT was produced in >95% purity. Molecular modeling of INFT revealed comparable binding energies to IPPI at site-1 of the Tau fibril with an affinity of IC₅₀ = 7.3 × 10⁻⁸ M. Binding of [¹²⁵I]INFT correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. The ratio of average grey matter (GM) [¹²⁵I]INFT in AD versus CN was found to be 5.9, and AD GM/white matter (WM) = 2.5. Specifically bound [¹²⁵I]INFT to Tau in AD brains was displaced by IPPI (>90%). Monoamine oxidase inhibitor deprenyl had no effect and clorgyline had little effect on [¹²⁵I]INFT binding. [¹²⁵I]INFT is a less lipophilic imaging agent for Tau in AD. Full article

Alzheimer’s disease (AD) is one of the leading causes of death worldwide, with no definitive diagnosis or known cure. The aggregation of Tau protein into neurofibrillary tangles (NFTs), which contain straight filaments (SFs) and paired helical filaments (PHFs), is a major hallmark of AD. Graphene quantum dots (GQDs) are a type of nanomaterial that combat many of the small-molecule therapeutic challenges in AD and have shown promise in similar pathologies. In this study, two sizes of GQDs, GQD7 and GQD28, were docked to various forms of Tau monomers, SFs, and PHFs. From the favorable docked poses, we simulated each system for at least 300 ns and calculated the free energies of binding. We observed a clear preference for GQD28 in the PHF6 (³⁰⁶VQIVYK³¹¹) pathological hexapeptide region of monomeric Tau, while GQD7 targeted both the PHF6 and PHF6* (²⁷⁵VQIINK²⁸⁰) pathological hexapeptide regions. In SFs, GQD28 had a high affinity for a binding site that is available in AD but not in other common tauopathies, while GQD7 behaved promiscuously. In PHFs, GQD28 interacted strongly near the protofibril interface at the putative disaggregation site for epigallocatechin-3-gallate, and GQD7 largely interacted with PHF6. Our analyses revealed several key GQD binding sites that may be used for detecting, preventing, and disassembling the Tau aggregates in AD. Full article

Intracellular tau accumulation is a hallmark pathology of Alzheimer’s disease (AD) and other tauopathies. Tau protein, in the hyperphosphorylated form, is the component of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in AD. Blocking tau aggregation and/or phosphorylation is currently a promising strategy for AD treatment. Here, we elucidate that quercetagitrin, a natural compound derived from African marigold (Tagetes erecta), could inhibit tau aggregation and reduce tau phosphorylation at multiple disease-related sites in vitro. Moreover, the in vivo effect of quercetagitrin was assessed in P301S-tau transgenic via oral administration. The compound treatment restored the cognitive deficits and neuron loss in the mice. The formation of NFTs and tau phosphorylations in the hippocampus and cortex of the mice was also prevented by the compound. Moreover, quercetagitrin feeding displayed neuroinflammation protection through the inhibition of NF-κB activation in the mice. Together, our data reveal that quercetagitrin possesses the potential to further develop as a therapeutic medicine for AD and other tauopathies. Full article

The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer’s disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)—tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [¹⁸F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations. Full article

Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms the neurofibrillary tangles. Intracellular and extracellular accumulation of different tau isoforms, including dimers, oligomers, paired helical filaments and tangles, lead to a highly heterogenous group of diseases named “Tauopathies”. About twenty-six different types of tauopathy diseases have been identified that have different clinical phenotypes or pathophysiological characteristics. Although all these diseases are identified by tau aggregation, they are distinguishable based on the specific tau isoforms, the affected cell types and the brain regions. The neuropathological and phenotypical heterogeneity of these diseases impose significant challenges for discovering new diagnostic and therapeutic strategies. Here, we review the recent literature on tau protein and the pathophysiological mechanisms of tauopathies. This article mainly focuses on physiologic and pathologic tau and aims to summarize the upstream and downstream events and discuss the current diagnostic approaches and therapeutic strategies. Full article

The identification of protein aggregates as biomarkers for neurodegeneration is an area of interest for disease diagnosis and treatment development. In this work, we present novel super luminescent conjugated polyelectrolyte molecules as ex vivo sensors for tau-paired helical filaments (PHFs) and amyloid-β (Aβ) plaques. We evaluated the use of two oligo-p-phenylene ethynylenes (OPEs), anionic OPE₁²⁻ and cationic OPE₂⁴⁺, as stains for fibrillar protein pathology in brain sections of transgenic mouse (rTg4510) and rat (TgF344-AD) models of Alzheimer’s disease (AD) tauopathy, and post-mortem brain sections from human frontotemporal dementia (FTD). OPE₁²⁻ displayed selectivity for PHFs in fluorimetry assays and strong staining of neurofibrillary tangles (NFTs) in mouse and human brain tissue sections, while OPE₂⁴⁺ stained both NFTs and Aβ plaques. Both OPEs stained the brain sections with limited background or non-specific staining. This novel family of sensors outperformed the gold-standard dye Thioflavin T in sensing capacities and co-stained with conventional phosphorylated tau (AT180) and Aβ (4G8) antibodies. As the OPEs readily bind protein amyloids in vitro and ex vivo, they are selective and rapid tools for identifying proteopathic inclusions relevant to AD. Such OPEs can be useful in understanding pathogenesis and in creating in vivo diagnostically relevant detection tools for neurodegenerative diseases. Full article

Cellular internalization and the spreading of misfolded tau have become increasingly important for elucidating the mechanism of Tau pathology involved in Alzheimer’s disease (AD). The low-density lipoprotein-related receptor 1 (LRP1) has been implicated in the internalization of fibrillar tau. In this work, we utilized homology modeling to model the Cluster 2 domain of LRP1 and determined that a 23-amino-acid sequence is involved in binding to paired helical filaments (PHF) of Tau. Fourteen short peptide segments derived from this ectodomain region were then designed and docked with PHF Tau. Molecular dynamics studies of the optimal peptides bound to PHF Tau demonstrated that the peptides formed critical contacts through Lys and Gln residues with Tau. Based on the computational results, flow cytometry, AFM, SPR analysis and CD studies were conducted to examine binding and cellular internalization. The results showed that the peptide sequence TauRP (1–14) (DNSDEENCES) was not only associated with fibrillar Tau but was also able to mitigate its cellular internalization in LRP1-expressed HEK-293 cells. Preliminary docking studies with Aβ (1–42) revealed that the peptides also bound to Aβ (1–42). While this study focused on the CCR2 domain of LRP1 to design peptide sequences to mitigate Tau internalization, the work can be extended to other domains of the LRP1 receptor or other receptors to examine if the cellular internalization of fibrillar Tau can be deterred. These findings show that short peptides derived from the LRP1 receptor can alter the internalization of its ligands. Full article

Complex yarns with helical wrapping structure show auxetic effect under axial tension and a wide perspective application. Experimental results suggested that initial helical angle was one of the most important structural parameters. However, the experimental method was limited and could not effectively explain the deformation behavior or auxetic mechanism. A finite element model of the helical auxetic yarn was built and used to analyze the interactive relationship between the two components and the stress distribution mode. The effectiveness and accuracy of the model was first verified by comparing with the experimental results. The simulation results showed that the complex yarn with initial helical angle of 14.5° presented the maximum negative Poisson’s ratio of −2.5 under 5.0% axial strain. Both the contact property between the two components and the radial deformability of the elastic core filament were key factors of the auxetic property. When the contact surfaces were completely smooth and the friction coefficient μ was set to 0, the complex yarn presented non-auxetic behavior. When the Poisson’s ratio of the core filament was 0, the complex yarn showed greater auxetic effect. During the axial stretching, the tensile stress was mainly distributed in the wrap filament, which led to structural deformation and auxetic behavior. A pair of auxetic yarns showed pore effect and high expansion under axial strain. Thus, it may be necessary to consider new weaving structures and preparation methods to obtain the desired auxetic property and application of auxetic yarns. Full article

Alzheimer’s disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice. Full article

The tau protein, a soluble protein associated with microtubules, which is involved in the assembly and stabilization of cytoskeletal elements, was found to form neurofibrillary tangles in different neurodegenerative diseases. Insoluble tau aggregates were observed to be organized in paired helical filaments (PHFs) and straight filaments (SFs). Recently, two small sequences (306–311 and 275–280) in the microtubule-binding region (MTBR), named PHF6 and PHF6*, respectively, were found to be essential for tau aggregation. Since a possible therapeutic approach consists of impairing amyloid formation either by stabilizing the native proteins or reducing the level of amyloid precursors, here we use synchrotron radiation circular dichroism (SRCD) at Diamond B23 beamline to evaluate the inhibitory effects of two small molecules, trehalose and ceftriaxone, against the aggregation of a small peptide containing the PHF6* sequence. Our results indicate that both these molecules, ceftriaxone and trehalose, increased the stability of the peptide toward aggregation, in particular that induced by heparin. With trehalose being present in many fruits, vegetables, algae and processed foods, these results support the need to investigate whether a diet richer in trehalose might exert a protective effect toward pathologies linked to protein misfolding. Full article