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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.

The Jovian Auroral Distributions Experiment (JADE) on Juno provides the critical in situ measurements of electrons and ions needed to understand the plasma energy particles and processes that fill the Jovian magnetosphere and ultimately produce its strong aurora. JADE is an instrument suite that includes three essentially identical electron sensors (JADE-Es), a single ion sensor (JADE-I), and a highly capable Electronics Box (EBox) that resides in the Juno Radiation Vault and provides all necessary control, low and high voltages, and computing support for the four sensors. The three JADE-Es are arrayed 120 ∘ apart around the Juno spacecraft to measure complete electron distributions from ∼0.1 to 100 keV and provide detailed electron pitch-angle distributions at a 1 s cadence, independent of spacecraft spin phase. JADE-I measures ions from ∼5 eV to ∼50 keV over an instantaneous field of view of 270 ∘ ×90 ∘ in 4 s and makes observations over all directions in space each 30 s rotation of the Juno spacecraft. JADE-I also provides ion composition measurements from 1 to 50 amu with m /Δ m ∼2.5, which is sufficient to separate the heavy and light ions, as well as O+ vs S+, in the Jovian magnetosphere. All four sensors were extensively tested and calibrated in specialized facilities, ensuring excellent on-orbit observations at Jupiter. This paper documents the JADE design, construction, calibration, and planned science operations, data processing, and data products. Finally, the Appendix describes the Southwest Research Institute [SwRI] electron calibration facility, which was developed and used for all JADE-E calibrations. Collectively, JADE provides remarkably broad and detailed measurements of the Jovian auroral region and magnetospheric plasmas, which will surely revolutionize our understanding of these important and complex regions.

Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including 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,” based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5–267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6–1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as “Low CTE” or “High CTE” for use in future clinical, pathological, and molecular studies.

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.

Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. The protein DJ1, encoded by the PARK7 gene, is causally linked to development of early-onset PD. Here the authors observed that the loss of DJ1 function in midbrain organoids led to astrocyte dysfunction, impairing protein clearance, accumulation of α-synuclein.

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

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.

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.

Communication between glial cells has a profound impact on the pathophysiology of Alzheimer’s disease (AD). We reveal here that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 ( PLXNB1 ), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation. Additionally, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD. The axon guidance receptor Plexin-B1 regulates the cellular interaction of peri-plaque astrocytes with microglia to affect the pathophysiology of Alzheimer’s disease.