In Alzheimer’s disease (AD) brain, exposure of axons to Aβ causes pathogenic changes that spread retrogradely by unknown mechanisms, affecting the entire neuron. We found that locally applied Aβ1-42 ...initiates axonal synthesis of a defined set of proteins including the transcription factor ATF4. Inhibition of local translation and retrograde transport or knockdown of axonal Atf4 mRNA abolished Aβ-induced ATF4 transcriptional activity and cell loss. Aβ1-42 injection into the dentate gyrus (DG) of mice caused loss of forebrain neurons whose axons project to the DG. Protein synthesis and Atf4 mRNA were upregulated in these axons, and coinjection of Atf4 siRNA into the DG reduced the effects of Aβ1-42 in the forebrain. ATF4 protein and transcripts were found with greater frequency in axons in the brain of AD patients. These results reveal an active role for intra-axonal translation in neurodegeneration and identify ATF4 as a mediator for the spread of AD pathology.
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•Locally applied Aβ1-42 triggers recruitment of mRNAs into axons and local translation•ATF4 is locally synthesized and retrogradely transported in response to Aβ1-42•Knockdown of axonal Atf4 mRNA reduces Aβ1-42-induced neurodegeneration in vivo•ATF4 transcript and protein levels are increased in axons in the brain of AD patients
Axonal exposure to β-amyloid elicits the local synthesis of the transcription factor ATF, which is retrogradely transported to the neuron cell bodies where it triggers a transcriptional response leading to cell death.
The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, ...including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this ...complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative ...conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.
Titan's lower atmosphere has long been known to harbor organic aerosols (tholins) presumed to have been formed from simple molecules, such as methane and nitrogen (CH₄ and N₂). Up to now, it has been ...assumed that tholins were formed at altitudes of several hundred kilometers by processes as yet unobserved. Using measurements from a combination of mass/charge and energy/charge spectrometers on the Cassini spacecraft, we have obtained evidence for tholin formation at high altitudes (~1000 kilometers) in Titan's atmosphere. The observed chemical mix strongly implies a series of chemical reactions and physical processes that lead from simple molecules (CH₄ and N₂) to larger, more complex molecules (80 to 350 daltons) to negatively charged massive molecules (~8000 daltons), which we identify as tholins. That the process involves massive negatively charged molecules and aerosols is completely unexpected.
A survey of the bulk plasma ion properties observed by the Cassini Plasma Spectrometer instrument over roughly the first 4.5 years of its mission in orbit around Saturn is presented. The moments ...(density, temperature, and flow velocity) of the plasma distributions below 50 keV have been computed by numerical integration of the observed counts in the “Singles” (non‐mass‐resolved) data, partitioned into species on the basis of concurrent determinations of the composition from the time‐of‐flight data. Moments are presented for three main species: H+, W+ (water group ions), and ions with m/q = 2, which are presumed to be H2+. While the survey extends to radial distances of 30 RS and thus includes some solar wind or magnetosheath values, our principal interest is the large‐scale spatial variation of the magnetospheric plasma properties, so we focus attention on radial distances inside of 17 RS. Principal findings include the following: (1) the densities of all three components are highly variable but are generally well organized by dipole L and magnetic latitude; (2) the density of ions with m/q = 2 varies from a few percentage of the H+ density in the inner magnetosphere to a maximum of several tens of percentage near the orbit of Titan, suggesting that Titan is an important source for H2+ in the outer magnetosphere; (3) water group ions are the dominant population in the inner magnetosphere, but only within ∼3 RS of the equatorial plane because of their strong centrifugal confinement; (4) derived latitudinal scale heights are largest for the light ions and generally increase with radial distance; (5) the L dependence of the calculated temperatures is not consistent with adiabatic transport but is in fair agreement with the expectations for plasma originating from ion pickup; (6) in agreement with the findings of Sergis et al. (2010), inside of L ∼ 11, the particle pressure is dominated by ions with energies below a few keV; (7) the derived flow velocities reveal the global circulation pattern of relatively dense populations in the magnetosphere, with no evidence for return circulation from the nightside to the dayside beyond ∼20 RS; and (8) the azimuthal flow speeds are typically less than full corotation over the entire L range examined, varying from ∼50% to 70% of full corotation.
Titan's ionosphere contains a rich positive ion population including organic molecules. Here, using CAPS electron spectrometer data from sixteen Titan encounters, we reveal the existence of negative ...ions. These ions, with densities up to ∼100 cm−3, are in mass groups of 10–30, 30–50, 50–80, 80–110, 110–200 and 200+ amu/charge. During one low encounter, negative ions with mass per charge as high as 10,000 amu/q are seen. Due to their unexpectedly high densities at ∼950 km altitude, these negative ions must play a key role in the ion chemistry and they may be important in the formation of organic‐rich aerosols (tholins) eventually falling to the surface.
The interaction of Io with the corotating magnetosphere of Jupiter is known to produce Alfvén wings that couple the moon to Jupiter's ionosphere. We present first results from a new numerical model ...to describe the propagation of these Alfvén waves in this system. The model is cast in magnetic dipole coordinates and includes a dense plasma torus that is centered around the centrifugal equator. Results are presented for two density models, showing the dependence of the interaction on the magnetospheric density. Model results are presented for the case when Io is near the centrifugal and magnetic equators as well as when Io is at its northernmost magnetic latitude. The effect of the conductance of Jupiter's ionosphere is considered, showing that a long auroral footprint tail is favored by high Pedersen conductance in the ionosphere. The current patterns in these cases show a U‐shaped footprint due to the generation of field‐aligned current on the Jupiter‐facing and Jupiter‐opposed sides of Io, which may be related to the structure in the auroral footprint seen in the infrared by Juno. A model for the development of parallel electric fields is introduced, indicating that the main auroral footprints of Io can generate parallel potentials of up to 100 kV.
Plain Language Summary
Jupiter's moon Io generates electrical currents when it passes through Jupiter's magnetic field. These currents take the form of fluctuations in the magnetic field lines, much like the waves on a stringed musical instrument. Due to the motion of Io, these waves follow behind Io and bounce back and forth between Jupiter and the dense ionized gas emitted by Io. This process creates auroral emissions that can be observed, e.g., with the Hubble Space Telescope.
Key Points
The spacing of the main auroral spots in Io's footprint tail depends on the density profile assumed as well as the magnetic latitude of Io
Partial reflections at the boundary of the Io plasma torus lead to secondary reflections and weaker auroral spots between the main spots
The length of the auroral tail depends on the ionospheric conductance at Jupiter, with higher conductances leading to longer tails
Tau is a highly abundant and multifunctional brain protein that accumulates in neurofibrillary tangles (NFTs), most commonly in Alzheimer's disease (AD) and primary age-related tauopathy. Recently, ...microRNAs (miRNAs) have been linked to neurodegeneration; however, it is not clear whether miRNA dysregulation contributes to tau neurotoxicity. Here, we determined that the highly conserved brain miRNA miR-219 is downregulated in brain tissue taken at autopsy from patients with AD and from those with severe primary age-related tauopathy. In a Drosophila model that produces human tau, reduction of miR-219 exacerbated tau toxicity, while overexpression of miR-219 partially abrogated toxic effects. Moreover, we observed a bidirectional modulation of tau levels in the Drosophila model that was dependent on miR-219 expression or neutralization, demonstrating that miR-219 regulates tau in vivo. In mammalian cellular models, we found that miR-219 binds directly to the 3'-UTR of the tau mRNA and represses tau synthesis at the post-transcriptional level. Together, our data indicate that silencing of tau by miR-219 is an ancient regulatory mechanism that may become perturbed during neurofibrillary degeneration and suggest that this regulatory pathway may be useful for developing therapeutics for tauopathies.
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem ...cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
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•Tau and P-tau accumulation and autophagy disruption in tau-V337M organoids•Accelerated synaptic maturation and loss of glutamatergic cortical-layer neurons•Altered ELAVL4 expression, dysregulated splicing, accelerated synaptic maturation•Rescue of susceptibility to glutamatergic toxicity by PIKFYVE inhibitor apilimod
Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod.
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