There is a fundamental gap in understanding the consequences of tau–ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau–ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01970-9) contains supplementary material, which is available to authorized users.

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.

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Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human AD proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy.

To the Editor, Myocarditis as a rare complication after coronavirus disease 2019 (COVID-19) mRNA vaccination in adolescents and young adults has been recently reported; 1,2 however, follow-up data was lacking. MethodsThis is an observational case series of patients who were diagnosed with myocarditis after mRNA COVID-19 vaccination. The clinical characteristics, short-term (4-6 months) follow-up cardiac imaging and clinical outcomes are described.

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Background Cryptococcal meningitis (CM) is a life-threatening condition that requires prompt recognition and management. With high morbidity in mind, we elected to compare the key CSF analysis, blood culture and serum cryptococcal antigen (CrAg) to prognosticate the probability of mortality in this population. Table 1. Comparison of demographics, serum and CSF analysis Methods We retrospectively reviewed all charts of patients admitted to our tertiary care center from 10/2005 to 10/2017. Inclusion criteria encompassed patients with positive CSF CrAg, positive CSF cultures, India ink, cytopathology, or CSF cell count >5 with CNS symptoms, positive serum CrAg titer or blood cultures. Results Sixty patients who met the inclusion criteria were divided into the survivor (n=41) and the non-survivor (n=19) groups based on the inpatient mortality. There was no difference in age, sex, and immune status between the two groups. The median CSF nucleated cell counts in the non-survivor group was 39 cells/µL with median lymphocyte 59.5% whereas in the survivor group was 72 cells/µL with median lymphocyte 76% (P< 0.001 and 0.04 respectively). The median CSF glucose was 27 mg/ml in the non-survivor compared to 35 mg/ml in the survivor group (P=0.02). Median CSF CrAg was higher at 1:1024 in the non-survivor group whereas the survivor group was 1:256 (P < 0.01). CSF opening pressure (cm H2O), blood culture, and serum CrAg level were not statistically significant between the two groups. Conclusion Low CSF cell count, low glucose, and high CSF CrAg were independently associated with inpatient mortality in CM. This is in line with the prior findings. A novel finding in this study is significantly decreased median CSF lymphocyte % in the non-survivor group. Serum CrAg titer, positive blood cultures, and median CSF protein were not statistically significant between the two groups. However, a study with a larger sample size may be needed to confirm these findings. Disclosures All Authors: No reported disclosures