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A simple microfluidic device based on the use of a paper platform modified with AuNPs was developed. The ALP-like CeO 2 nanozyme first converts p-nitrophenyl phosphate (pNPP) to PNP. Fluorescence detection of Tau-441 was proposed based on the inner filter effect (IFE) of n-doped graphene quantum dots (NGQDs) and p-nitrophenol (PNP). [Display omitted] • A novel device based on the use of a paper platform modified with AuNPs was developed. • Fluorescence detection of Tau protein (Tau-441) was proposed based on the inner filter effect (IFE) of n-doped graphene quantum dots (NGQDs). • The ALP-like CeO 2 nanozyme first converts p-nitrophenyl phosphate (pNPP) to p-nitrophenol (PNP) for the rapid analysis of Tau-441 content in human serum samples. The advancement of Alzheimer's disease (AD) is directly correlated to the phosphorylation damage of Tau protein (Tau-441), which is considered the most reliable indicator for early detection of AD. Nevertheless, the concentration of Tau-441 in human serum remains considerably low. To address this issue, a paper-based fluorescence immunosensor based on internal filter effect (IFE) was developed for the detection Tau-441. The microfluidic paper-based channel was prepared and modified with a gold layer to attach primary antibodies and increase the sensitivity of the sensor. All at once, Au@CeO 2 nanorods was employed as a fluorescence probe to hydrolyze p-nitrophenyl phosphate (pNPP), which generates hydrolyzed product p-nitrophenol (PNP) can reduce or quench the fluorescence intensity of N-doped graphene quantum dots (NGQDs). The immunosensor was designed to detect an increase in the amount of Tau-441 collected as the fluorescence intensity of NGQDs decreased. The developed sensor demonstrated satisfactory results in clinical serum samples, offering a promising concept for an immunoassay tagged with nanozymes for early detection of AD. Overall, this microfluidic paper-based fluorescent immunosensor has the potential to improve early diagnosis of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid – β extracellular plaques and tau interfibrillar tangles, leading to memory loss, cognitive decline, and behavioral changes. With dementia posing a growing global health concern, there is an urgent need for comprehensive strategies to address its challenges. The economic burden of dementia is projected to rise significantly, emphasizing the necessity for collaborative efforts in research and healthcare. In the United States alone, millions are affected by AD , with prevalence increasing with age and even affecting younger individuals. The complexity of AD involves intricate biological processes, including the aggregation of amyloid beta, oxidative stress, and metal ion dysregulation. Metal ions, particularly those from copper, iron, and zinc, play pivotal roles in AD pathology, influencing Aβ deposition and tau protein accumulation. Current treatments offer symptomatic relief but do not address the underlying disease mechanisms. This paper explores the potential of various chelating compounds to target metal ions involved in AD pathology. N -acylhydrazones, morpholine, chrysin, quinoline, oxindole, cyclam, catechol-based, and quinazolinone-based derivatives show promising chelation activity and therapeutic effects. Metal chelation therapy offers a targeted approach to AD treatment by addressing the core pathology. By selectively binding to metal ions implicated in disease progression, chelators may minimize side effects associated with broad-spectrum treatments. Additionally, chelators may offer neuroprotective effects beyond metal binding, further enhancing their therapeutic potential. Overall, metal chelation therapy presents a promising strategy in combating AD , with the potential to significantly impact disease progression and improve patient outcomes. [Display omitted] • Description of metal ions pathology, involved in progress of Alzheimer's Disease (AD). • N -acylhydrazones, morpholine, chrysin, quinoline, oxindole, cyclam, catechol and quinazolinone ligands as chelating agents. • The review presents potential therapeutic effects of chelating compounds in Alzheimer's Disease treatment. [ABSTRACT FROM AUTHOR]

• Multimodal strategies and interventions, e.g. healthy lifestyle (dietary and physical activity), can be recommended for treatment of Alzheimer's disease (AD). • Gene study and gene-based therapy with a critical role in the detection and cure of AD will have a fundamental role. • Attempts to enhance clinical results are focused on several main areas including design and detection of more effective carrier molecules, selection of the best gene delivery methods, and detection of novel therapeutic targets. Neurodegenerative diseases such as Alzheimer's disease (AD) are still an important issue for scientists because it is difficult to cure with the available molecular medications and conventional treatments. Due to the complex nature of the brain structures and heterogeneous morphological and physiological properties of neuronal cells, interventions for cerebral-related disorders using surgical approaches, and classical and ongoing treatments remain hard for physicians. Furthermore, the development of newly designed medications attempts to target AD are not successful in improving AD, because abnormalities of tau protein, aggregation of amyloid β (Aβ) peptide, inflammatory responses, etc lead to advanced neurodegeneration processes that conventional treatments cannot stop them. In recent years, novel diagnostic strategies and therapeutic approaches have been developed to identify and cure early pathological events of AD. Accordingly, many gene-based therapies have been developed and introduce the therapeutic potential to prevent and cure AD. On the other hand, genetic investigations and postmortem assessments have detected a large number of factors associated with AD pathology. Also, genetically diverse animal models of AD help us to detect and prioritize novel resilience mechanisms. Hence, gene therapy can be considered an effective and powerful tool to identify and treat human diseases. Ultimately, gene study and gene-based therapy with a critical role in the detection and cure of various human disorders will have a fundamental role in our lives forever. This scientific review paper discusses the present status of different therapeutic strategies, particularly gene-based therapy in treating AD, along with its challenges. [ABSTRACT FROM AUTHOR]

Tau protein is an intrinsically disordered protein that plays a key role in Alzheimer's disease (AD). In brains of AD patients, Tau occurs abnormally phosphorylated and aggregated in neurofibrillary tangles (NFTs). Together with Tau, 14-3-3 proteins – abundant cytosolic dimeric proteins – were found colocalized in the NFTs. However, so far, the molecular mechanism of the process leading to pathological changes in Tau structure as well as the direct involvement of 14-3-3 proteins are not well understood. Here, we aimed to reveal the effects of phosphorylation by protein kinase A (PKA) on Tau structural preferences and provide better insight into the interaction between Tau and 14-3-3 proteins. We also addressed the impact of monomerization-inducing phosphorylation of 14-3-3 at S58 on the binding to Tau protein. Using multidimensional nuclear magnetic resonance spectroscopy (NMR), chemical cross-linking analyzed by mass spectrometry (MS) and PAGE, we unveiled differences in their binding affinity, stoichiometry, and interfaces with single-residue resolution. We revealed that the interaction between 14-3-3 and Tau proteins is mediated not only via the 14-3-3 amphipathic binding grooves, but also via less specific interactions with 14-3-3 protein surface and, in the case of monomeric 14-3-3, also partially via the exposed dimeric interface. In addition, the hyperphosphorylation of Tau changes its affinity to 14-3-3 proteins. In conclusion, we propose quite complex interaction mode between the Tau and 14-3-3 proteins. • Complex characterization of PKA phosphorylation of 2N4R Tau protein • PKA phosphorylation of Tau disrupts paper-clip conformation and induces extension. • Phospho-Tau binds besides the amphipathic groove also 14-3-3ζ protein surface. • Tau and 14-3-3ζ dimer form complexes with stoichiometry 1:2 and 2:4 (per monomer). • Interaction of Tau with monomeric 14-3-3ζ is more transient than with 14-3-3ζ dimer. [ABSTRACT FROM AUTHOR]

Tau protein is an intrinsically disordered protein that plays a key role in Alzheimer's disease (AD). In brains of AD patients, Tau occurs abnormally phosphorylated and aggregated in neurofibrillary tangles (NFTs). Together with Tau, 14-3-3 proteins – abundant cytosolic dimeric proteins – were found colocalized in the NFTs. However, so far, the molecular mechanism of the process leading to pathological changes in Tau structure as well as the direct involvement of 14-3-3 proteins are not well understood. Here, we aimed to reveal the effects of phosphorylation by protein kinase A (PKA) on Tau structural preferences and provide better insight into the interaction between Tau and 14-3-3 proteins. We also addressed the impact of monomerization-inducing phosphorylation of 14-3-3 at S58 on the binding to Tau protein. Using multidimensional nuclear magnetic resonance spectroscopy (NMR), chemical cross-linking analyzed by mass spectrometry (MS) and PAGE, we unveiled differences in their binding affinity, stoichiometry, and interfaces with single-residue resolution. We revealed that the interaction between 14-3-3 and Tau proteins is mediated not only via the 14-3-3 amphipathic binding grooves, but also via less specific interactions with 14-3-3 protein surface and, in the case of monomeric 14-3-3, also partially via the exposed dimeric interface. In addition, the hyperphosphorylation of Tau changes its affinity to 14-3-3 proteins. In conclusion, we propose quite complex interaction mode between the Tau and 14-3-3 proteins. • Complex characterization of PKA phosphorylation of 2N4R Tau protein • PKA phosphorylation of Tau disrupts paper-clip conformation and induces extension. • Phospho-Tau binds besides the amphipathic groove also 14-3-3ζ protein surface. • Tau and 14-3-3ζ dimer form complexes with stoichiometry 1:2 and 2:4 (per monomer). • Interaction of Tau with monomeric 14-3-3ζ is more transient than with 14-3-3ζ dimer. [ABSTRACT FROM AUTHOR]