Total Tau Protein Levels Research Articles

Rosuvastatin attenuates total-tau serum levels and increases expression of miR-124-3p in dyslipidemic Alzheimer's patients: a historic cohort study.

microRNAs are candidate diagnostic biomarkers for Alzheimer's disease. This study aimed to compare Silymarin with Rosuvastatin and placebo on total-Tau protein level and expression levels of microRNAs and TGF-β and COX-2 in Alzheimer's patients with secondary dyslipidemia. 36 mild AD patients with dyslipidemia were divided into three groups of 12. The first group received silymarin (140mg), the second group received placebo (140mg), and the third group recieved Rosuvastatin (10mg). Tablets were administered three times a day for Six months. The blood samples of the patients were collected before and after the intervention and the serum was separated. Using the RT-qPCR method, the expression levels of miR-124-3p and miR-125b-5p were assessed, and the serum levels of total-Tau, TGF-β, and COX-2 enzyme were measured using the ELISA method. Data were analyzed with SPSS software. In this study, the level of Δtotal-Tau was significantly lower in the Rosuvastatin group compared to the placebo (P = 0.038). Also, a significant reduction in the level of ΔTGF-β was observed in the Silymarin to Rosuvastatin group (p = 0.046) and ΔmiR-124-3p was significantly increased in the Rosuvastatin compared to the placebo group (p = 0.044). Rosuvastatin outperformed silymarin in decreasing Δtotal-Tau serum levels and enhancing expression of ΔmiR-124-3p, attributed to Rosuvastatin's capacity to lower cholesterol levels and inflammation concurrently. Conversely, silymarin was more effective than Rosuvastatin in reducing levels of ΔTGF-β. Serum miR-124-3p could serve as a promising diagnostic biomarker and a new therapeutic focus in AD.

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis.

Background and Objectives: Recent findings suggest that neurodegeneration starts early in the course of multiple sclerosis (MS) and significantly contributes to the progression of patients' disability. Tau is a microtubule-binding protein that is known to play a role in the pathophysiology of many neurodegenerative disorders. Newly emerging data on tau protein-induced neurodegenerative processes and its possible involvement in MS suggest that it may be involved in the pathology of early-stage MS. Therefore, this study aimed to test this hypothesis in patients with newly diagnosed MS. Materials and Methods: Cerebrospinal fluid (CSF) was collected from 19 patients with newly diagnosed MS and 19 control subjects. All MS patients underwent neurological examination, lumbar punction, and brain magnetic resonance imaging (MRI). CSF concentrations of total and phosphorylated tau (phospho-tau-181) protein were measured using commercial enzyme-linked immunosorbent assay kits. Results: The total tau concentration was significantly higher in the CSF of MS patients compared to controls (141.67 pg/mL, IQR 77.79-189.17 and 68.77 pg/mL, IQR 31.24-109.17, p = 0.025). In MS patients, the total tau protein positively correlated with total CSF protein (r = 0.471, p = 0.048). Significantly higher total tau concentration was measured in MS patients with higher lesion load in brain MRI (≥9 versus <9 lesions; 168.33 pg/mL, IQR 111.67-222.32 and 73.33 pg/mL, IQR -32.13-139.29-, p = 0.021). The CSF concentration of phospho-tau-181 protein was below the detection limit in both MS and control subjects. Conclusions: The concentration of total tau protein level is elevated, whereas phospho-tau-181 is undetectable in the CSF of patients with early-stage MS.

Modulating Effects of Vitamin K2 on Oxidative Stress Induced Organelle Damage in Alzheimer’s Disease

AbstractBackgroundCurrent treatment strategies for AD are either involved in an improved amyloid‐beta precursor protein (APP) processing via inhibition and/or activation of enzymatic machinery. Whereas, others drug regimen includes the use of putative tau kinase inhibitors, microtubule stabilizers and tau immunotherapies. Moreover, therapies to combat oxidative stress are currently being devised because oxidative stress plays a major role innneurodegeneration. Interestingly, current studies are being focused on the screening of bioactive compounds for their effect on prevention of Aβ formation, oxidative stress reduction and targeting organelle dysfunction, which will potentiate the use of bioactive compounds to prevent AD in early stages. Vitamin K2 is one of the bioactive compounds which has gained importance for its role as an antioxidant.MethodTo understand the neuroprotective effect of vitamin K2 during metabolic complications, SH‐SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose dependent manner, followed by the post treatment of vitamin K2 for 5 h. Modulating effects of vitamin K2 on cell viability, Lactate Dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR) p‐IRE1α, GSK 3α/β, total tau and Aβ 42 were studied.ResultVitamin K2 significantly reduced the neuronal cell death by inhibiting the cytotoxicity, ROS levels and helped in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p‐IRE1 α, thus showing its significant role in inhibiting chronic ER stress mediated UPR and eventually apoptosis. In addition, Vitamin K2 significantly downregulated the expression of GSK 3 α/β together with the levels of total tau protein, with petite effect on secreted Aβ 42 levels.ConclusionVitamin K2 ameliorated mitochondrial damage, ER stress and tauopathy mediated neuronal cell death, highlighting its role as a novel antioxidative therapeutics targeting related cellular processes.

Associations between neuropsychiatric symptoms and ADRD serum biomarkers in Mexican American and non‐Hispanic white adults with mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is a heterogenous diagnostic category with trajectories ranging from reversion to unimpaired cognition to progression to dementia. Neuropsychiatric symptoms such as depression and irritability are common and influence quality of life of patients and caregivers. The role of neuropsychiatric symptoms on disease biology, presentation, and course remains poorly understood. The goal of this study was to evaluate the associations between neuropsychiatric symptoms and serum ADRD biomarkers in Mexican American and non‐Hispanic white participants diagnosed with MCI.MethodParticipants from the Texas Alzheimer’s Research and Care Consortium underwent a blood draw and clinical evaluation, including psychopathological and cognitive assessments. Diagnoses of MCI were adjudicated in consensus reviews. The presence and severity of neuropsychiatric symptoms were assessed by informant report using the Neuropsychiatric Inventory (NPI). Serum levels of total tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were assessed using Simoa HD‐X Analyzer. Associations between NPI total score and individual items with serum biomarker levels were assessed using linear regression adjusted for age and sex.ResultA total of 425 participants (mean age: 71 ± 9 years, 62% female, 74% Mexican American) had a diagnosis of MCI and serum ADRD biomarkers (Table 1). Total NPI score was not associated with total tau (ß = 0.002, p = 0.609), NfL (ß = 0.001, p = 0.658), or GFAP (ß = 0.001, p = 0.777). However, endorsement of appetite changes was associated with higher NfL (ß = 0.077, p = 0.006) and GFAP (ß = 0.088, p = 0.002) levels. Stratified analyses indicated associations of appetite changes with serum NfL (ß = 0.108, p = 0.002) and GFAP (ß = 0.095, p = 0.003) in Mexican Americans, but not in non‐Hispanic whites (NfL: ß = 0.022, p = 0.633, GFAP: ß = 0.102, p = 0.066).There were no other significant associations between individual items on the NPI with serum biomarkers (p&gt;0.05, Bonferroni adjustment p±0.003).ConclusionWithin Mexican American adults with MCI, changes in appetite were associated with higher serum NFL and GFAP levels. As elevations in circulating NfL and GFAP levels are associated with ADRD pathology and accelerated disease progression, appetite changes, a non‐invasive and easily discernible behavioral phenotype, may predict higher likelihood of worsening cognitive course. Future longitudinal studies will be necessary to confirm predictive utility of appetite changes for disease progression.

Targeted plasma eQTL and pQTL to identify potential novel biomarkers for Alzheimer’s Disease in African Americans

AbstractBackgroundGiven the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non‐Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD‐risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers.MethodsIn 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS), we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU.ResultsOf the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p&lt;0.05) with plasma transcript/protein levels and with AD‐risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1, and TLR4, and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE‐ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex.ConclusionsPlasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

PD‐L1 blockade therapeutic effect in Tau P301S (line PS19) mouse model of tauopathy

AbstractBackgroundThere is a growing understanding that Alzheimer’s disease (AD) and tauopathies are not merely brain‐centric conditions, but encompass also dysfunction of the peripheral immune system that impacts disease onset and progression. We have previously shown, in several mouse models of AD, that blockade of the PD‐1/PD‐L1 immune checkpoint pathway facilitates homing of specialized immune cells to the brain, where these cells mitigate different pathomechanisms, ultimately leading to function improvement. Here, we tested PD‐L1 blockade in the Tau P301S (line PS19) mouse model of tauopathy.MethodsTau P301S mice were treated with anti‐PD‐L1 antibody, or isotype control, and tested for the functional effect of the treatment on parameters of cognitive performance and brain pathology, at different time points after treatment. Pharmacokinetic and pharmacodynamic events following treatment were evaluated to monitor the peripheral and central immune response. Treatment effects were also evaluated in TREM2 knockout Tau P301S mice.ResultsDose‐dependent effect of anti‐PD‐L1 treatment was detected at 14‐ and 28‐days post‐treatment, with respect to cognitive performance of PS19 mice, as measured by T maze task. At the different timepoints following treatment we found reduction in cerebrospinal fluid total tau protein levels, and reduction in cortical phosphorylated tau (Ser404) protein levels. The functional effect on improvement of cognitive performance following anti‐PD‐L1 administration was also observed in TREM2 knockout Tau P301S mice, suggesting that the therapeutic effect of anti‐PD‐L1, is independent of TREM2 expression.ConclusionsPD‐L1 blockade evokes an immune response that leads to functional improvement on cognitive performance and reduced brain pathology in Tau P301S mice. These findings, taken together with our previous reports of anti‐PD‐L1 therapeutic effect in other AD or tauopathy mouse models, substantiate the generalization of this treatment approach ‐ targeting the peripheral immune system in order to drive brain tissue repair in neurodegenerative conditions.

Implications of Tau Dysregulation in Huntington's Disease and Potential for New Therapeutics.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The disease, characterized by motor, cognitive, and psychiatric impairments, is caused by the expansion of a CAG repeat in the huntingtin gene. Despite the discovery of the mutation in 1993, no disease-modifying treatments are yet available. Understanding the molecular and cellular mechanisms involved in HD is therefore crucial for the development of novel treatments. Emerging research has found that HD might be classified as a secondary tauopathy, with the presence of tau insoluble aggregates in late HD. Increased total tau protein levels have been observed in both HD patients and animal models of HD. Tau hyperphosphorylation, the main feature of tau pathology, has also been investigated and our own published results suggest that the protein phosphorylation machinery is dysregulated in the early stages of HD in R6/1 transgenic mice, primarily in the cortex and striatum. Protein phosphorylation, catalysed by kinases, regulates numerous cellular mechanisms and has been shown to be dysregulated in other neurodegenerative disorders, including Alzheimer's disease. While it is still unclear how the mutation in the huntingtin gene leads to tau dysregulation in HD, several hypotheses have been explored. Evidence suggests that the mutant huntingtin does not directly interact with tau, but instead interacts with tau kinases, phosphatases, and proteins involved in tau alternative splicing, which could result in tau dysregulation as observed in HD. Altogether, there is increasing evidence that tau is undergoing pathological changes in HD and may be a good therapeutic target.

Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau181 and Total Tau in Plasma of Young Elite Soccer Players

Head impacts resulting in traumatic brain injury (TBI) lead to the elevation of phosphorylated tau protein (p-tau181) in plasma. To our knowledge, this study is the first to investigate dynamics of p-tau181 levels and the ratio of p-tau181 to total tau in individuals after nonconcussive head impacts. To determine the association of repetitive low-intensity head impacts on p-tau181 and total tau protein levels in the plasma of young adult elite soccer players and assess the possible association of head impacts with focused attention and cognitive flexibility. In this cohort study, young elite soccer players performed intense physical activity with and without heading the ball. The study was conducted at a university facility in Slovakia from October 1, 2021, to May 31, 2022. Eligible participants were selected based on similarities in demographic variables, excluding those with a history of TBI. The primary study outcomes were the levels of total tau protein and p-tau181 in plasma samples and the cognitive status of the study participants. A total of 37 male athletes participated in the study (mean [SD] age: exercise group, 21.6 [1.6] years; heading group, 21.2 [1.5] years). We found significantly elevated levels of total tau and p-tau181 in the plasma of soccer players 1 hour after physical exercise (tau, 1.4-fold; 95% CI, 1.2-1.5; P < .001; p-tau181, 1.4-fold; 95% CI, 1.3-1.5, P < .001) and repetitive head impacts (tau, 1.3-fold; 95% CI, 1.2-1.4; P < .001; p-tau181, 1.5-fold; 95% CI, 1.4-1.7 P < .001). The ratio of p-tau181 to tau was significantly higher 1 hour after exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold; 95% CI, 1.1-1.3; P = .002). Performance in cognitive tests revealed a significant decline in focused attention and cognitive flexibility after physical exercise and heading training; physical exercise of higher intensity without heading training was associated with a greater negative cognitive performance than heading only. In this cohort study of young elite soccer players, the elevation of p-tau181 and tau was observed after acute intense physical activity and nonconcussive repetitive head impacts. The increase of p-tau181 levels relative to tau after 24 hours indicated an acute enrichment of phosphorylated tau fraction in the periphery when compared with preimpact levels; an imbalance of tau proteins may have long-lasting consequences in the brain of head-impacted individuals.

Correlation between cognitive impairment and serum phosphorylated tau181 protein in patients with preeclampsia.

To study the cognitive function status, serum phosphorylated tau181 (P-tau181) protein level, and total tau (T-tau) protein level in patients with preeclampsia (PE), pregnant healthy controls (PHCs), and non-pregnant healthy controls (NPHCs), and to research their feasibility as serum biomarkers for evaluating cognitive functional impairment in PE patients. Sixty-eight patients with PE, 48 NPHCs, and 30 PHCs were included. Cognitive functional status was assessed using standardized Symbol Digit Modalities Test (SDMT) and Montreal Cognitive Assessment (MoCA) scales. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of serum P-tau181 and T-tau protein. The concentration of serum P-tau181 and T-tau protein were compared by one-way analysis of variance in the three groups of subjects. The correlation between P-tau181, T-tau, and SDMT was explore by multiple linear regression analysis. The areas under the receiver operating characteristic (ROC) curves of serum P-tau181 and SDMT were calculated to predict the cognitive level of subjects. PE patients significantly had lower scores on SDMT (47.97 ± 7.54) and MoCA (28.00 ± 2.00) than normotensive PHCs (30.00 ± 1.25, 54.73 ± 8.55, respectively). The significant difference was found in serum P-tau181 protein levels among the three groups [H(K) = 19.101, P < 0.001]. Serum P-tau181 was thicker in PE patients than PHCs or NPHCs (both P < 0.05). According to the ROC curve, T-tau had no statistical significance in predicting the ability of cognizance, while P-tau181 and SDMT had. The DeLong test showed that P-tau181 was better than T-tau in predicting the ability of cognizance (P < 0.05). The patients with PE have occurred the decline of cognitive function during pregnancy. The high level of serum P-tau181 can be used as a clinical laboratory indication for non-invasive assessment of cognitive functional impairment in PE patients.

Evidence of Plasma Biomarkers Indicating High Risk of Dementia in Cognitively Normal Subjects with a History of Stroke, a Family History of Alzheimer’s Disease, Diabetes Mellitus, End‐stage Renal Disease and Obstructive Sleep Apnea

AbstractBackgroundSubjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration.MethodIn this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1‐42 and total tau protein (T‐Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end‐stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty‐seven healthy controls (HCs) were enrolled.ResultThe measured concentrations of plasma Aβ1‐42 were 14.26±1.42, 15.43±1.76, 15.52±1.60, 19.74±2.92, 16.52±0.59, 15.97±0.54 and 20.06±3.09 pg/ml in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T‐Tau were 15.13±3.62, 19.29±8.01, 17.93±6.26, 19.74±2.92, 21.54±2.72, 20.17±2.77 and 41.24±14.64 pg/ml. The plasma levels of Aβ1‐42 and T‐Tau in the PS, ADFH, diabetes, ESRD and OSA groups were relatively high compared to HC group but were lower than AD group.ConclusionThis evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers.

Cerebrospinal fluid markers of inflammation and brain injury in Lyme neuroborreliosis- a prospective follow-up study.

The purpose of this study was to evaluate levels and kinetics of cerebrospinal fluid (CSF) markers of inflammation and brain injury in patients with Lyme neuroborreliosis (LNB). Adult patients with clinically suspected LNB were enrolled, in a prospective clinical study in the South East of Sweden. Patients were classified according to the European Federation of Neurological Societies' guidelines. Definite cases of LNB were re-examined one month later including a repeat CSF investigation. Routine laboratory parameters were investigated along with CSF levels of neurodegenerative markers glial fibrillary acidic protein (GFAp), total tau (t-tau) and neurofilament light protein (NFL), as well as neuroinflammatory markers soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL-40 and CXCL13. Non-LNB served as controls. An additional comparison group consisted of spinal anesthesia subjects (SAS) without known central nervous system conditions. CSF levels of sTREM2 and CXCL13 were elevated in definite LNB patients at diagnosis compared with non-LNB patients (p<0.001) and SAS (p≤0.01). In addition, CSF levels of sTREM2, YKL-40 and CXCL13 rapidly declined in at follow-up after antibiotic treatment. In contrast, CSF levels of GFAp and t-tau did not differ across LNB groups, and did not change after treatment. Although in a limited number of LNB patients, the results indicate a predominance of microglial and neuroinflammatory involvement rather than parenchymal CNS injury in CSF at diagnosis of LNB with a prompt decline after antibiotic treatment. The findings provide pathogenetic insights and may be of value in differential diagnosis of CSF findings.

Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis.

Background and purposeThis study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS).MethodsOne hundred forty‐three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array.ResultsNfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive–behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001).ConclusionsNfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.

Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer's Dementia: A Case-Control Study.

BackgroundNeural autoantibody-associated dementia (NABD) is an increasing phenomenon in memory clinics with a high impact on later therapy. Biomarkers are lacking that differentiate this type of dementia from neurodegenerative dementia such as Alzheimer’s dementia (AD). Our aim is to analyze neurodegeneration markers and their relationship to progressing cognitive dysfunction in NABD and AD to test for tools differentiating these two forms of dementia prior to neural autoantibody testing.MethodsIn our retrospective, observational study, we investigated 14 patients with dementia and serum and/or cerebrospinal fluid (CSF) neural autoantibodies as well as 14 patients with AD by relying on recent CSF and clinical criteria for AD. Patient files were checked for psychopathology, neuropsychological test performance, autoimmune indicators, CSF, and MRI results.ResultsOur patient groups did not differ in their psychopathology, autoimmune indicators, or MRI profile. The progression of cognitive dysfunction [as measured by the difference in Mini-Mental State Examination (MMSE) scores since disease onset, and the yearly progression rate (MMSE loss/per year)] did not vary significantly between groups. Total tau protein was significantly higher in AD patients than NABD patients revealing no signs of Alzheimer’s disease pathology in their CSF (p < 0.05). Total tau protein levels in CSF correlated with cognitive decline since disease onset (r = 0.38, p < 0.05) and yearly progression rates (r = 0.56, p < 0.005) in all patients.DiscussionOur results suggest that the progression of cognitive dysfunction as defined by MMSE does not seem to be an appropriate biomarker for distinguishing NABD from AD. However, the total tau protein level in CSF might be a relevant molecular biomarker that can indicate disease pathology and/or progression in both known AD and NABD, which is often accompanied by axonal degeneration. Total tau protein may be an additional diagnostic tool with which to differentiate anti-neural-associated dementia from AD if further research confirms these proof-of-concept findings in larger patient cohorts.

Loss of aly/ALYREF suppresses toxicity in both tau and TDP-43 models of neurodegeneration.

Neurodegenerative diseases with tau pathology, or tauopathies, include Alzheimer's disease and related dementia disorders. Previous work has shown that loss of the poly(A) RNA-binding protein gene sut-2/MSUT2 strongly suppressed tauopathy in Caenorhabditis elegans, human cell culture, and mouse models of tauopathy. However, the mechanism of suppression is still unclear. Recent work has shown that MSUT2 protein interacts with the THO complex and ALYREF, which are components of the mRNA nuclear export complex. Additionally, previous work showed ALYREF homolog Ref1 modulates TDP-43 and G4C2 toxicity in Drosophila melanogaster models. We used transgenic C. elegans models of tau or TDP-43 toxicity to investigate the effects of loss of ALYREF function on tau and TDP-43 toxicity. In C. elegans, three genes are homologous to human ALYREF: aly-1, aly-2, and aly-3. We found that loss of C. elegans aly gene function, especially loss of both aly-2 and aly-3, suppressed tau-induced toxic phenotypes. Loss of aly-2 and aly-3 was also able to suppress TDP-43-induced locomotor behavior deficits. However, loss of aly-2 and aly-3 had divergent effects on mRNA and protein levels as total tau protein levels were reduced while mRNA levels were increased, but no significant effects were seen on total TDP-43 protein or mRNA levels. Our results suggest that although aly genes modulate both tau and TDP-43-induced toxicity phenotypes, the molecular mechanisms of suppression are different and separated from impacts on mRNA and protein levels. Altogether, this study highlights the importance of elucidating RNA-related mechanisms in both tau and TDP-43-induced toxicity.

Evidence of plasma biomarkers indicating high risk of dementia in cognitively normal subjects

Subjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration. In this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1–42 and total tau protein (T-Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end-stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty-seven healthy controls (HCs) were enrolled. The measured concentrations of plasma Aβ1–42 were 14.26 ± 1.42, 15.43 ± 1.76, 15.52 ± 1.60, 16.15 ± 1.05, 16.52 ± 0.59, 15.97 ± 0.54 and 20.06 ± 3.09 pg/mL in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T-Tau were 15.13 ± 3.62, 19.29 ± 8.01, 17.93 ± 6.26, 19.74 ± 2.92, 21.54 ± 2.72, 20.17 ± 2.77 and 41.24 ± 14.64 pg/mL. The plasma levels of Aβ1–42 and T-Tau in were significantly higher in the PS, ADFH, diabetes, ESRD and OSA groups than controls (Aβ1–42 in PS: 15.43 ± 1.76 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.005; T-Tau in PS: 19.29 ± 8.01 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aβ1–42 in ADFH: 15.52 ± 1.60 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ADFH: 17.93 ± 6.26 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aβ1–42 in diabetes: 16.15 ± 1.05 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in diabetes: 19.74 ± 2.92 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aβ1–42 in ESRD: 16.52 ± 0.59 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ESRD: 21.54 ± 2.72 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aβ1–42 in OSA: 15.97 ± 0.54 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in OSA: 20.17 ± 2.77 vs. 15.13 ± 3.62 pg/mL, p < 0.001). This evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers.

Role of cerebrospinal fluid tau protein levels as a biomarker of brain injury in pediatric status epilepticus

Background Various biomarkers have been studied for predicting etiology and outcome in status epilepticus (SE); cerebrospinal fluid (CSF) total tau (t-tau) protein levels is foremost among them. Only handful of studies are available regarding role of t-tau in childhood SE. Methodology This prospective study was conducted in a tertiary care center of Northern India in children 6 months −12 years of age. The Cases were patients with convulsive status epilepticus (CSE) whereas Controls were patients without SE and normal CSF. The t-tau levels were done in CSF of both the groups. The outcome was assessed by GOS-E Peds score. Results A total of 50 (62% males) cases and 15 (67% males) controls were enrolled in the study. SE was generalized in 78% cases whereas 14% had refractory SE. Most common etiology of CSE was acute symptomatic (52%), followed by prolonged febrile seizure (24%), remote symptomatic group (14%), unknown etiology (8%) and progressive disorder (2%). Case fatality rate was 10%. Poor outcome was seen in 30% cases. Median (IQR) CSF t-tau levels was significantly lower 2.6 × 103 (0.5–9.4 × 103) pg/ml in cases vs 10.6 × 103 (6.0–14.2 × 103) pg/ml in controls (p = 0.004). There was no significant correlation seen between type, duration, etiology and response to antiepileptic drugs of SE with CSF t-tau levels. Also, no significant correlation of poor sensorium, outcome of SE and critical care needs with CSF t-tau levels was noted. Conclusion CSF t-tau is not a useful diagnostic or prognostic biomarker in pediatric SE.

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells.

Vitamin K2, known for its antioxidative and anti-inflammatory properties, can act as a potent neuroprotective molecule. Despite its action against mitochondrial dysfunction, the mechanism underlying the links between the protective effects of vitamin K2 and endoplasmic reticulum (ER) stress along with basal levels of total tau protein and amyloid-beta 42 (Aβ42) has not been elucidated yet. To understand the neuroprotective effect of vitamin K2 during metabolic complications, SH-SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose-dependent manner, followed by post-treatment of vitamin K2 for 5 h. The modulating effects of vitamin K2 on cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR), inositol requiring enzyme 1 (p-IRE1α), glycogen synthase kinase 3 (GSK3α/β), total tau and Aβ42 were studied. Results showed that vitamin K2 significantly reduces neuronal cell death by inhibiting cytotoxicity and ROS levels and helps in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p-IRE1α, thus showing its significant role in inhibiting chronic ER stress-mediated UPR and eventually cell death. In addition, vitamin K2 significantly down-regulated the expression of GSK3α/β together with the levels of total tau protein, with a petite effect on secreted Aβ42 levels. These results suggested that vitamin K2 alleviated mitochondrial damage, ER stress and tauopathy-mediated neuronal cell death, which highlights its role as new antioxidative therapeutics targeting related cellular processes.

Estrogens still represent an attractive therapeutic approach for Alzheimer's disease.

Estrogens still represent an attractive therapeutic approach for Alzheimer's disease.

Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients.

Background and aimsPatients infected with SARS-CoV-2 range from asymptomatic, to mild, moderate or severe disease evolution including fatal outcome. Thus, early predictors of clinical outcome are highly needed. We investigated markers of neural tissue damage as a possible early sign of multisystem involvement to assess their clinical prognostic value on survival or transfer to intensive care unit (ICU). MethodsWe collected blood from 104 patients infected with SARS-CoV-2 the day of admission to the emergency room and measured blood neurofilament light chair (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau protein levels.ResultsWe found that NfL, GFAP, and tau were significantly increased in patients with fatal outcome, while NfL and UCH-L1 in those needing ICU transfer. ROC and Kaplan–Meier curves indicated that total tau levels at admission accurately predict mortality.ConclusionsBlood neural markers may provide additional prognostic value to conventional biomarkers used to predict COVID-19 outcome. Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-021-10595-6.

Neuroprotective Effect of Epalrestat on Hydrogen Peroxide-Induced Neurodegeneration in SH-SY5Y Cellular Model.

Epalrestat (EPS) is a brain penetrant aldose reductase inhibitor, an approved drug currently used for the treatment of diabetic neuropathy. At near-plasma concentration, EPS induces glutathione biosynthesis, which in turn reduces oxidative stress in the neuronal cells. In this study, we found that EPS reduces neurodegeneration by inhibiting reactive oxygen species (ROS)-induced oxidative injury, mitochondrial membrane damage, apoptosis and tauopathy. EPS treatment up to 50 μM did not show any toxic effect on SH-SY5Y cell line (neuroblastoma cells). However, we observed toxic effect at a concentration of 100 μM and above. At 50 μM concentration, EPS showed better antioxidant activity against H2O2 (100 μM)-induced cytotoxicity, ROS formation and mitochondrial membrane damage in retinoic acid-differentiated SH-SY5Y cell line. Furthermore, our study revealed that 50 μM of EPS concentration reduced the glycogen synthase kinase-3 β (GSK3-β) expression and total tau protein level in H2O2 (100 μM)-treated cells. Findings from this study confirms the therapeutic efficacy of EPS on regulating Alzheimer's disease (AD) by regulating GSK3-β and total tau proteins phosphorylation, which helped to restore the cellular viability. This process could also reduce toxic fibrillary tangle formation and disease progression of AD. Therefore, it is our view that an optimal concentration of EPS therapy could decrease AD pathology by reducing tau phosphorylation through regulating the expression level of GSK3-β.