Tau Protein Research Articles

Integrated Ultrasound-Enrichment and Machine Learning in Colorimetric Lateral Flow Assay for Accurate and Sensitive Clinical Alzheimer's Biomarker Diagnosis.

The colloidal gold nanoparticle (AuNP)-based colorimetric lateral flow assay (LFA) is one of the most promising analytical tools for point-of-care disease diagnosis. However, the low sensitivity and insufficient accuracy still limit its clinical application. In this work, a machine learning (ML)-optimized colorimetric LFA with ultrasound enrichment is developed to achieve the sensitive and accurate detection of tau proteins for early screening of Alzheimer's disease (AD). The LFA device is integrated with a portable ultrasonic actuator to rapidly enrich microparticles using ultrasound, which is essential for sample pre-enrichment to improve the sensitivity, followed by ML algorithms to classify and predict the enhanced colorimetric signals. The results of the undiluted serum sample testing show that the protocol enables efficient classification and accurate quantification of the AD biomarker tau protein concentration with an average classification accuracy of 98.11% and an average prediction accuracy of 99.99%, achieving a limit of detection (LOD) as sensitive as 10.30pgmL-1. Further point-of-care testing (POCT) of human plasma samples demonstrates the potential use of LFA in clinical trials. Such a reliable lateral flow immunosensor with high precision and superb sensing performance is expected to put LFA in perspective as an AD clinical diagnostic platform.

Comprehensive evaluation of pathogenic protein accumulation in fibroblasts from all subtypes of Sanfilippo disease patients

Sanfilippo disease is a lysosomal storage disorder from the group of mucopolysaccharidoses (MPS), characterized by storage of glycosaminoglycans (GAGs); thus, it is also called MPS type III. The syndrome is divided into 4 subtypes (MPS III A, B, C and D). Despite the storage of the same GAG, heparan sulfate (HS), the course of these subtypes can vary considerably. Here, we comprehensively evaluated the levels of protein aggregates (APP, β-amyloid, p-tau, α-synuclein, TDP43) in fibroblasts derived from patients with all MPS III subtypes, and tested whether lowering GAG levels results in a decrease in the levels of the investigated proteins and the number of aggregates they form. Elevated levels of APP, β-amyloid, tau, and TDP43 proteins were evident in all MPS III subtypes, and elevated levels of p-tau and α-synuclein were demonstrated in all subtypes except MPS IIIC. These findings were confirmed in the neural tissue of MPS IIIB mice. Fluorescence microscopy studies also indicated a high number of protein aggregates formed by β-amyloid and tau in all cell lines tested, and a high number of aggregates of p-tau, TDP43, and α-synuclein in all lines except MPS IIIC. Reduction of GAG levels by genistein led to the decrease of levels of all tested proteins and their aggregates except α-synuclein, indicating a relationship between GAG levels and those of some protein aggregates. This work describes for the first time the problem of deposited protein aggregates in all subtypes of Sanfilippo disease and suggests that GAGs are partly responsible for the formation of protein aggregates.

Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.

Animal and computational models of Alzheimer's disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD. In these asymptomatic individuals, we found that Aβ depositions colocalize with accelerated neurophysiological activity. In those also presenting medial-temporal tau pathology, linear mixed effects of Aβ and tau depositions indicate a shift toward slower neurophysiological activity, which was also linked to cognitive decline. We conclude that early Aβ and tau depositions relate synergistically to human cortical neurophysiology and subsequent cognitive decline. Our findings provide insight into the multifaceted neurophysiological mechanisms engaged in the preclinical phases of AD.

Sleep Fragmentation and Sleep-Wake Cycle Dysregulation Are Associated with Cerebral Tau Burden in Patients with Mild Cognitive Impairment due to Alzheimer's Disease: A Case Series.

Although disturbed sleep is frequent in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD), the association between sleep and tau pathology is unclear. This case series focused on measuring the sleep-wake rhythm over 7 days through actigraphy in patients diagnosed with MCI due to AD. Further, the association between sleep-wake cycle and tau deposition measured through positron emission tomography (PET) was explored. This case series included 6 MCI due to AD patients (2 women and 4 men, mean age 73.17±5.53 years), who completed neuropsychological testing, 7-day actigraphy, and tau PET imaging with radiolabeled compounds aimed to estimate the density and distribution of aggregated tau neurofibrillary tangles in the brain. The case series indicated that patients with MCI due to AD who exhibited greater tau deposition in the frontal, parietal, and limbic regions, as well as in the precuneus and olfactory regions, also showed increased sleep fragmentation, as measured through actigraphy. The findings from this case series suggest a potential link between tau deposition in key brain regions associated with AD and both sleep fragmentation and sleep-wake cycle dysregulation in a small sample of patients with MCI due to AD. These preliminary results warrant further investigation in larger, more comprehensive studies to confirm and expand upon these findings.

A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination

Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/− mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.

Exploring the Association between Pro-Inflammation and the Early Diagnosis of Alzheimer’s Disease in Buccal Cells Using Immunocytochemistry and Machine Learning Techniques

The progressive aging of the global population and the high impact of neurodegenerative diseases, such as Alzheimer’s disease (AD), underscore the urgent need for innovative diagnostic and therapeutic strategies. AD, the most prevalent neurodegenerative disorder among the elderly, is expected to affect 75 million people in developing countries by 2030. Despite extensive research, the precise etiology of AD remains elusive due to its heterogeneity and complexity. The key pathological features of AD, including amyloid-beta plaques and hyperphosphorylated tau protein, are established years before clinical symptoms appear. Recent studies highlight the pivotal role of neuroinflammation in AD pathogenesis, with the chronic activation of the brain’s immune system contributing to the disease’s progression. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, are elevated in AD and mild cognitive impairment (MCI) patients, suggesting a strong link between peripheral inflammation and CNS degeneration. There is a pressing need for minimally invasive, cost-effective diagnostic methods. Buccal mucosa cells and saliva, which share an embryological origin with the CNS, show promise for AD diagnosis and prognosis. This study integrates cellular observations with advanced data processing and machine learning to identify significant biomarkers and patterns, aiming to enhance the early diagnosis and prevention strategies for AD.

Multifaceted neuroprotective approach of Trolox in Alzheimer's disease mouse model: targeting Aβ pathology, neuroinflammation, oxidative stress, and synaptic dysfunction.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Aβ1 - 42-induced AD mouse model. Aβ1 - 42 5μL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Aβ, phosphorylated tau (p-tau), and β-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (pNF-κB) and interleukin-1β (IL-1β), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.

Mesenchymal Stem Cell-Derived Exosomes as a Neuroregeneration Treatment for Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent kind of dementia and is a long-term degenerative disease. Pathologically, it is defined by the development of extracellular amyloid-β plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. This causes neuronal death, particularly in the hippocampus and cortex. Mesenchymal stem cell (MSC)-derived exosomes have been identified as possibly therapeutic and have promise for Alzheimer's disease due to their regenerative characteristics. A systematic retrieval of information was performed on PubMed. A total of 60 articles were found in a search on mesenchymal stem cells, exosomes, and Alzheimer's disease. A total of 16 ongoing clinical trials were searched and added from clinicaltrials.gov. We added 23 supporting articles to help provide information for certain sections. In total, we included 99 articles in this manuscript: 50 are review articles, 13 are preclinical studies, 16 are clinical studies, 16 are ongoing clinical trials, and 4 are observational studies. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on mesenchymal stem cell exosomes for Alzheimer's disease were searched on clinicaltrials.gov. Several experimental investigations have shown that MSC-Exo improves cognitive impairment in rats. In this review paper, we summarized existing understanding regarding the molecular and cellular pathways behind MSC-Exo-based cognitive function restoration, with a focus on MSC-Exo's therapeutic potential in the treatment of Alzheimer's disease. AD is a significant health issue in our culture and is linked to several important neuropathological characteristics. Exosomes generated from stem cells, such as mesenchymal stem cells (MSCs) or neural stem cells (NSCs), have been examined more and more in a variety of AD models, indicating that they may be viable therapeutic agents for the treatment of diverse disorders. Exosome yields may be increased, and their therapeutic efficacy can be improved using a range of tailored techniques and culture conditions. It is necessary to provide standardized guidelines for exosome manufacture to carry out excellent preclinical and clinical research.

Gut microbiota metabolites: potential therapeutic targets for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology. In this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD. The gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including β-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance. Despite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.

Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer’s disease

The cellular prion protein (PrPC) plays many roles in the developing and adult brain. In addition, PrPC binds to several amyloids in oligomeric and prefibrillar forms and may act as a putative receptor of abnormal misfolded protein species. The role of PrPC in tau seeding and spreading is not known. In the present study, we have inoculated well-characterized sarkosyl-insoluble fractions of sporadic Alzheimer’s disease (sAD) into the brain of adult wild-type mice (Prnp+/+), Prnp0/0 (ZH3 strain) mice, and mice over-expressing the secreted form of PrPC lacking their GPI anchor (Tg44 strain). Phospho-tau (ptau) seeding and spreading involving neurons and oligodendrocytes were observed three and six months after inoculation. 3Rtau and 4Rtau deposits from the host tau, as revealed by inoculating Mapt0/0 mice and by using specific anti-mouse and anti-human tau antibodies suggest modulation of exon 10 splicing of the host mouse Mapt gene elicited by exogenous sAD-tau. However, no tau seeding and spreading differences were observed among Prnp genotypes. Our results show that PrPC does not affect tau seeding and spreading in vivo.

Chronic Traumatic Encephalopathy: A Comprehensive Narrative Review of Its Biomarkers.

Chronic traumatic encephalopathy (CTE) is a progressive and fatal neurological disorder linked to repeated traumatic brain injuries (TBIs), including concussions and blows to the head. This condition is characterized by the accumulation of abnormally structured hyperphosphorylated tau proteins (p-tau), forming neurofibrillary tangles, astrocytic tangles, and neurites in the brain. CTE is often diagnosed post-mortem, making it challenging to diagnose and predict its progression in living individuals. Despite recent advancements, no definitive pathological, radiological, or neurobiological marker consistently shows promise in diagnosing and predicting the disease. This review aims to summarize the available techniques and advancements in imaging-based, genetic, neuropsychological, and fluid biomarkers for CTE, evaluating their specificity and sensitivity. It will also highlight the limitations of each marker in diagnosing CTE and provide future research directions to enhance the accuracy of CTE diagnosis in living individuals.

Ventral Variant Posterior Cortical Atrophy with Occipito-temporal Accumulation of Tau Proteins/Astrocyte Gliosis.

A 73-year-old woman with posterior cortical atrophy (PCA) presented with progressive apperceptive visual agnosia, alexia, agraphia, ventral simultanagnosia, prosopagnosia, and allocentric (stimulus-centered) left-sided hemispatial neglect. All of these symptoms were attributed to damage to the bilateral occipito-temporal cortices, consistent with ventral variant PCA. While the Pittsburgh compound B uptake was extensively distributed throughout the occipito-parietal (dorsal) and occipito-temporal (ventral) areas, the THK5351 (ligand binding to tau aggregates/astrocyte gliosis) accumulation was limited to the ventral area. These findings suggest that local accumulation of tau proteins and/or astrocyte gliosis over the occipito-temporal cortices can result in ventral variant PCA.

Live-cell visualization of tau aggregation in human neurons

Alzheimer’s disease (AD) and more than twenty other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule-associated protein tau (MAPT). Although tau aggregation correlates with AD symptomology, the specific tau species, i.e., monomers, soluble oligomers, and insoluble aggregates that induce neurotoxicity are incompletely understood. We developed a light-responsive tau protein (optoTAU) and used viscosity-sensitive AggFluor probes to investigate the consequence(s) of tau aggregation in human neurons and identify modifiers of tau aggregation in AD and other tauopathies. We determined that optoTAU reproduces biological and structural properties of tau aggregation observed in human brains and the pathophysiological transition in tau solubility in live cells. We also provide proof-of-concept for the utilization of optoTAU as a pharmacological platform to identify modifiers of tau aggregation. These findings have broad implications for the characterization of aggregation-prone proteins and investigation of the complex relationship between protein solubility, cellular function, and disease progression.

Insights into the Role of microRNAs as Clinical Tools for Diagnosis, Prognosis, and as Therapeutic Targets in Alzheimer's Disease.

Neurodegenerative diseases (NDDs) are a diverse group of neurological disorders characterized by alterations in the structure and function of the central nervous system. Alzheimer's disease (AD), characterized by impaired memory and cognitive abilities, is the most prevalent type of senile dementia. Loss of synapses, intracellular aggregation of hyperphosphorylated tau protein, and extracellular amyloid-β peptide (Aβ) plaques are the hallmarks of AD. MicroRNAs (miRNAs/miRs) are single-stranded ribonucleic acid (RNA) molecules that bind to the 3' and 5' untranslated regions of target genes to cause post-transcriptional gene silencing. The brain expresses over 70% of all experimentally detected miRNAs, and these miRNAs are crucial for synaptic function and particular signals during memory formation. Increasing evidence suggests that miRNAs play a role in AD pathogenesis and we provide an overview of the role of miRNAs in synapse formation, Aβ synthesis, tau protein accumulation, and brain-derived neurotrophic factor-associated AD pathogenesis. We further summarize and discuss the role of miRNAs as potential therapeutic targets and biomarkers for AD detection and differentiation between early- and late-stage AD, based on recent research. In conclusion, altered expression of miRNAs in the brain and peripheral circulation demonstrates their potential as biomarkers and therapeutic targets in AD.

The ameliorative potential of metformin against aluminum-induced neurotoxicity: Insights from in vitro studies.

Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder, often referred to as type 3 diabetes, due to its strong association with insulin resistance. Chronic exposure to aluminum, a known neurotoxin, has been identified as a significant risk factor in the development and progression of AD. This study explores the potential of metformin, a common anti-diabetic drug, to mitigate aluminum-induced neurotoxicity in an in vitro model of AD. Our findings reveal that metformin significantly reduces oxidative stress markers such as malonaldehyde, carbonyl groups, and reactive oxygen species while enhancing antioxidant defenses. Metformin modulates critical signaling pathways, including glycogen synthase kinase 3 beta (GSK3-β)/RAC-alpha serine/threonine protein kinase (RAC-alpha serine/threonine protein kinase (Akt1)/protein phosphatase 2A (PP2A) and Wnt/β-catenin, decreasing Tau protein levels and promoting neurogenesis. These results suggest that metformin may offer a novel therapeutic approach for AD, particularly in cases where aluminum exposure is a contributing factor.

P38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.

CircSLC4A7 in resistant-cells-derived exosomes promotes docetaxel resistance via the miR-1205/MAPT axis in prostate cancer.

Prostate cancer (PCa) is a high-mortality cancer. Docetaxel (DCT) combined with second-generation anti-androgens is considered the golden standard therapy for PCa, whose application is limited for DCT resistance (DR). Therefore, exploring the mechanism of DR is of great importance. In this study, PCa cell lines of PC3 and DU145 were employed, and DR cells were constructed by treatment with graded DCT. CircSLC4A7, miR-1205, and microtubule-associated protein tau (MAPT) transfections were established. Cell counting kit-8 assay was performed to evaluate the cell activity and IC50 of DCT. After being treated with DCT, DR was assessed by colony formation assay, flow cytometry analysis, and terminal transferase-mediated UTP nick end-labeling assay. Real-time quantitative PCR and western blotting analysis evaluated the expression levels of genes. The dual-luciferase reporter gene assay verified the miR-1205 binding sites with circSLC4A7 and MAPT. An animal experiment was performed to assess the tumor growth influenced by circSLC4A7. After conducting DR cells and isolated exosomes, we found that not only co-culture with DR cells but also treatment with DR cells' exosomes would promote the DR of normal cells. Moreover, circSLC4A7 was highly expressed in DR cells and their exosomes. CircSLC4A7 overexpression enhanced DR, represented as raised IC50 of DCT, increased colony formation, and decreased cell apoptosis after DCT treatment, while circSLC4A7 knockdown had the opposite effect. MiR-1205 was confirmed as a circSLC4A7-sponged miRNA and miR-1205 inhibitor reversed the effect of sh-circSLC4A7. MAPT was further identified as a target of miR-1205 and had a similar effect with circSLC4A7. The effect of circSLC4A7 on DR was also confirmed by xenograft experiments. Collectively, circSLC4A7 in resistant-cells-derived exosomes promotes DCT resistance of PCa via miR-1205/MAPT axis, which may provide a new treatment strategy for DR of PCa.

Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP

Microtubule-associated protein tau (MAPT/tau) accumulates in a family of neurodegenerative diseases, including Alzheimer’s disease (AD). In disease, tau is aberrantly modified by post-translational modifications (PTMs), including hyper-phosphorylation. However, it is often unclear which of these PTMs contribute to tau’s accumulation or what mechanisms might be involved. To explore these questions, we focus on a cleaved proteoform of tau (tauC3), which selectively accumulates in AD and was recently shown to be degraded by its direct binding to the E3 ubiquitin ligase, CHIP. Here, we find that phosphorylation of tauC3 at a single residue, pS416, is sufficient to weaken its interaction with CHIP. A co-crystal structure of CHIP bound to the C-terminus of tauC3 reveals the mechanism of this clash, allowing design of a mutation (CHIPD134A) that partially restores binding and turnover of pS416 tauC3. We confirm that, in our models, pS416 is produced by the known AD-associated kinase, MARK2/Par-1b, providing a potential link to disease. In further support of this idea, an antibody against pS416 co-localizes with tauC3 in degenerative neurons within the hippocampus of AD patients. Together, these studies suggest a molecular mechanism for how phosphorylation at a discrete site contributes to accumulation of a tau proteoform.

Elevated cerebrospinal fluid neuronal injury biomarkers within 24 hours of onset in infection-triggered acute encephalopathy compared to complex febrile seizures

ObjectiveThis study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD). MethodsPediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups. ResultsTotal of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml). ConclusionsThe elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury.