Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases

Tau is a microtubule-associated protein, which is highly expressed in the central nervous system as well as ocular neurons and stabilizes microtubule structure. It is a phospho-protein being moderately phosphorylated under physiological conditions but its abnormal hyperphosphorylation or some post-phosphorylation modifications would result in a pathogenic condition, microtubule dissociation, and aggregation. The aggregates can induce neuroinflammation and trigger some pathogenic cascades, leading to neurodegeneration. Taking these together, targeting pathogenic tau employing tau immunotherapy may be a promising therapeutic strategy in fighting with cerebral and ocular neurodegenerative disorders

Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases

Tau is a microtubule-associated protein, which is highly expressed in the central nervous system as well as ocular neurons and stabilizes microtubule structure. It is a phospho-protein being moderately phosphorylated under physiological conditions but its abnormal hyperphosphorylation or some post-phosphorylation modifications would result in a pathogenic condition, microtubule dissociation, and aggregation. The aggregates can induce neuroinflammation and trigger some pathogenic cascades, leading to neurodegeneration. Taking these together, targeting pathogenic tau employing tau immunotherapy may be a promising therapeutic strategy in fighting with cerebral and ocular neurodegenerative disorders

“Tau immunotherapy: Hopes and hindrances”

Alzheimer's disease (AD) is a progressive neurological disorder having two major pathological hallmarks: the extracellular senile plaques and intracellular neurofibrillary tangles composed of amyloid beta protein and hyperphosphorylated tau respectively. Removal of protein deposits from AD brains are the newer attempts for treating AD. The major developments in this direction have been the amyloid and tau based therapeutics. While senile plaque removal employing monoclonal antibodies (mAbs) restore brain function in mouse models of AD, tau has been recently introduced as the major neurodegenerative factor mediating neural cell death. So, several research groups have focused on tau therapy. So far, the outcome of tau immunotherapy has been promising and clearance of hyperphosphorylated tau has been shown to restore the brain function in animal models. But the point is which phosphorylated tau is the most critical form to be removed from the brain, especially because removal of physiologic tau can cause neurodegenerative consequence. Recently, we have shown that phosphorylated tau at Thr231 in the cis conformation is a very early driver of neurodegeneration and cis mAb treatment efficiently restores brain structure and function in TBI models. Because of efficient therapeutic effects in mice model of TBI and considering cis pT231-tau accumulation in AD brains, it could be a very good candidate for tau immunotherapy upon several tauopathy disorders including AD

Earlier Detection of Alzheimer’s Disease Based on a Novel Biomarker <em>cis</em> P-tau by a Label-Free Electrochemical Immunosensor

Early detection of cis phosphorylated tau (cis P-tau) may help as an effective treatment to control the progression of Alzheimer’s disease (AD). Recently, we introduced for the first time a monoclonal antibody (mAb) with high affinity against cis P-tau. In this study, the cis P-tau mAb was utilized to develop a label-free immunosensor. The antibody was immobilized onto a gold electrode and the electrochemical responses to the analyte were acquired by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The immunosensor was capable of selective detection of cis P-tau among non-specific targets like trans P-tau and major plasma proteins. A wide concentration range (10 × 10−14 M–3.0 × 10−9 M) of cis P-tau was measured in PBS and human serum matrices with a limit of detection of 0.02 and 0.05 pM, respectively. Clinical applicability of the immunosensor was suggested by its long-term storage stability and successful detection of cis P-tau in real samples of cerebrospinal fluid (CSF) and blood serum collected from human patients at different stages of AD. These results suggest that this simple immunosensor may find great application in clinical settings for early detection of AD which is an unmet urgent need in today’s healthcare services

Application of Pt@ZIF-8 nanocomposite-based electrochemical biosensor for sensitive diagnosis of tau protein in Alzheimer’s disease patients

Abstract Alzheimer’s disease (AD) is a progressive brain disorder characterized by the ongoing decline of brain functions. Studies have revealed the detrimental effects of hyperphosphorylated tau (p-tau) protein fibrils in AD pathogenesis, highlighting the importance of this factor in the early-stage detection of AD conditions. We designed an electrochemical immunosensor for quantitative detection of the cis conformation of the p-tau protein (cis-p-tau) employing platinum nanoparticles (Pt NPs) supported on zeolitic imidazolate frameworks (ZIF) for modifying the glassy carbon electrode (GCE) surface. Under optimum conditions, the immunosensor selectively and sensitively detected cis-p-tau within the broad linear range of 1 fg mL−1 to 10 ng mL−1 and the low limit of detection (LOD) of 1 fg mL−1 with desired reproducibility and stability. Furthermore, the fabricated immunosensor's performance was examined for the cis-p-tau analysis in the serum of AD patients, indicating its accuracy and feasibility for real-sample analysis. Notably, this is the first application of Pt@ZIF-8 nanocomposite in fabricating a valid immunosensor for selective cis-p-tau detection, even in the presence of trans-p-tau. It is worth mentioning that the enzyme-linked immunosorbent assay (ELISA) reference technique is not able to evaluate pico- or femtomolar concentrations of cis-p-tau, making the fabricated immunosensor superior for early-stage measurement and screening of AD

COVID-19 Vaccination Willingness and Acceptability in Multiple Sclerosis Patients:A Cross Sectional Study in Iran

Multiple sclerosis (MS) is a chronic, predominantly immune-mediated degenerative disease of the central nervous system. Due to prolonged use of immunomodulatory and immunosuppressive medications, vaccine hesitancy could be common among MS patients. Our main aim in the current study was to evaluate the willingness and acceptability of COVID-19 vaccination in patients with MS. In our multicenter cross-sectional questionnaire-based clinical study, 892 patients completed the questionnaire between May to June 2021. The questionnaire consisted of demographic data, MS disease-related factors, history of COVID-19 infection/vaccination, and any existing comorbidities. Statistical analysis was performed using SPSS software version 19. Overall, 68% of the participants expressed willingness to be vaccinated. Major causes of vaccine refusal in our patients were the fear of reducing the efficacy of disease modifying drugs (DMDs) upon vaccination as well as distrusting the vaccines and overestimation bias in the power of their innate immunity and potential COVID-19 resistance. Some demographic factors affected vaccination enthusiasm in our study. Our findings did not show significant correlation between the age and comorbidity and vaccine willingness. Only one-third of our patients received their vaccine information from healthcare providers. The majority of them received these data from official broadcasting channels and social media. However, despite several concerns, the willingness of COVD-19 vaccination in the Iranian MS patients is remarkable

cis p-tau: early driver of brain injury and tauopathy blocked by antibody

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury

Molecular interaction of fibrinogen with zeolite nanoparticles

International audienceFibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377–394), located in D-domain, showed the highest level of exposure compared to other sequences/residues