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Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters—neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington's disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer's disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson's disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51's role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51–heat-shock protein-(Hsp)90–p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease—the peroxisome proliferator-activated receptor-γ (PPARγ) and AKt. [ABSTRACT FROM AUTHOR]

Panax ginseng C.A. Meyer (P. ginseng) is one of the more common traditional Chinese medicines (TCMs). It contains numerous chemical components and exhibits a range of pharmacological effects. An enormous burden is placed on people's health and life by Alzheimer's disease (AD), a neurodegenerative condition. Recent research has shown that P. ginseng's chemical constituents, particularly ginsenosides, have a significant beneficial impact on the prevention and management of neurological disorders. To understand the current status of research on P. ginseng to improve AD, this paper discusses the composition of P. ginseng, its mechanism of action, and its clinical application. The pathogenesis of AD includes amyloid beta protein (Aβ) generation and aggregation, tau protein hyperphosphorylation, oxidant stress, neuroinflammation, mitochondrial damage, and neurotransmitter and gut microbiota disorders. This review presents the key molecular mechanisms and signaling pathways of the active ingredients in P. ginseng involved in improving AD from the perspective of AD pathogenesis. A P. ginseng-related signaling pathway network was constructed to provide effective targets for the treatment of AD. In addition, the application of spatial metabolomics techniques in studying P. ginseng and AD is discussed. In summary, this paper discusses research perspectives for the study of P. ginseng in the treatment of AD, including a systematic and in-depth review of the mechanisms of action of the active substances in P. ginseng, and evaluates the feasibility of applying spatial metabolomics in the study of AD pathogenesis and pharmacological treatment. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is the most common form of dementia. The cause of the disease is unknown, and it has no cure. Symptoms include cognitive decline, memory loss, and impairment of daily functioning. The pathological hallmarks of the disease are aggregation of plaques of amyloid-β (Aβ) and neurofibrillary tangles of tau proteins (τ), which can be detected in PET scans of the brain. The disease can remain asymptomatic for decades, while the densities of Aβ and τ continue to grow. Inflammation is considered an early event that drives the disease. In this paper, we develop a mathematical model that can produce simulated patterns of (Aβ,τ) seen in PET scans of AD patients. The model is based on the assumption that early inflammations, R and R¯ , drive the growth of Aβ and τ, respectively. Recently approved drugs can slow the progression of AD in patients, provided treatment begins early, before significant damage to the brain has occurred. In line with current longitudinal studies, we used the model to demonstrate how to assess the efficacy of such drugs when given years before the disease becomes symptomatic. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative condition marked by the progressive deterioration of cognitive abilities, memory impairment, and the accumulation of abnormal proteins, specifically beta-amyloid plaques and tau tangles, within the brain. Despite extensive research efforts, Alzheimer's disease remains without a cure, presenting a significant global healthcare challenge. Recently, there has been an increased focus on antibody-based treatments as a potentially effective method for dealing with Alzheimer's disease. This paper offers a comprehensive overview of the current status of research on antibody-based molecules as therapies for Alzheimer's disease. We will briefly mention their mechanisms of action, therapeutic efficacy, and safety profiles while addressing the challenges and limitations encountered during their development. We also highlight some crucial considerations in antibody-based treatment development, including patient selection criteria, dosing regimens, or safety concerns. In conclusion, antibody-based therapies present a hopeful outlook for addressing Alzheimer's disease. While challenges remain, the accumulating evidence suggests that these therapies may offer substantial promise in ameliorating or preventing the progression of this debilitating condition, thus potentially enhancing the quality of life for the millions of individuals and families affected by Alzheimer's disease worldwide. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia is a complex disease involving massive death of brain cells in full-term newborns. The most impressive consequence of perinatal asphyxia is a neurodegenerative brain injury called hypoxic–ischemic encephalopathy. Management of newborns after perinatal asphyxia is very difficult due to the lack of measurable biomarkers that would be able to assess the severity of the brain injury in the future, help in the selection of therapy, assess the results of treatment and determine the prognosis for the future. Thus, these limitations make long-term neurodevelopmental outcomes unpredictable during life. Quantifying biomarkers that can detect subclinical changes at a stage where routine brain monitoring or imaging is still mute would be a major advance in the care of neonates with brain neurodegeneration after asphyxia. Understanding the effect of perinatal asphyxia on changes in blood neurodegenerative biomarkers over time, which would be commonly used to assess the severity of postpartum encephalopathy, would be an important step in developing precision in predicting the consequences of brain injuries. We urgently need more accurate early predictive markers to guide clinicians when to use neuroprotective therapy. The needed neurodegenerative biomarkers may represent neuronal pathological changes that can be recognized by new technologies such as genomic and proteomic. Nevertheless, the simultaneous blood tau protein and various amyloid changes with the addition of an autophagy marker beclin 1 after perinatal asphyxia have not been studied. We decided to evaluate serum biomarkers of neuronal injury characteristic for Alzheimer's disease such as amyloid peptides (1-38, 1-40 and 1-42), tau protein and beclin 1, which can predict the progression of brain neurodegeneration in future. In this paper, we report for the first time the significant changes in the above molecules in the blood after asphyxia compared to healthy controls during the 1–7, 8–14 and 15+ days ELISA test. [ABSTRACT FROM AUTHOR]

Aims: Alzheimer's disease (AD) is a neurodegenerative disease with challenging early diagnosis and effective treatments due to its complex pathogenesis. AD patients are often diagnosed after the appearance of the typical symptoms, thereby delaying the best opportunity for effective measures. Biomarkers could be the key to resolving the challenge. This review aims to provide an overview of application and potential value of AD biomarkers in fluids, including cerebrospinal fluid, blood, and saliva, in diagnosis and treatment. Methods: A comprehensive search of the relevant literature was conducted to summarize potential biomarkers for AD in fluids. The paper further explored the biomarkers' utility in disease diagnosis and drug target development. Results: Research on biomarkers mainly focused on amyloid‐β (Aβ) plaques, Tau protein abnormal phosphorylation, axon damage, synaptic dysfunction, inflammation, and related hypotheses associated with AD mechanisms. Aβ42, total Tau (t‐Tau), and phosphorylated Tau (p‐Tau), have been endorsed for their diagnostic and predictive capability. However, other biomarkers remain controversial. Drugs targeting Aβ have shown some efficacy and those that target BACE1 and Tau are still undergoing development. Conclusion: Fluid biomarkers hold considerable potential in the diagnosis and drug development of AD. However, improvements in sensitivity and specificity, and approaches for managing sample impurities, need to be addressed for better diagnosis. [ABSTRACT FROM AUTHOR]

Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features of AD are memory decline and cognitive dysfunction, while PD mainly manifests as motor dysfunction such as limb tremors, muscle rigidity abnormalities, and slow gait. Abnormalities in cholesterol, sphingolipid, and glycerophospholipid metabolism have been demonstrated to directly exacerbate the progression of AD by stimulating Aβ deposition and tau protein tangles. Indirectly, abnormal lipids can increase the burden on brain vasculature, induce insulin resistance, and affect the structure of neuronal cell membranes. Abnormal lipid metabolism leads to PD through inducing accumulation of α-syn, dysfunction of mitochondria and endoplasmic reticulum, and ferroptosis. Great progress has been made in targeting lipid metabolism abnormalities for the treatment of AD and PD in recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, and monoclonal antibodies targeting apolipoprotein E (ApoE). This review comprehensively summarizes the involvement of dysregulated lipid metabolism in the pathogenesis of AD and PD, the application of Lipid Monitoring, and emerging lipid regulatory drug targets. A better understanding of the lipidological bases of AD and PD may pave the way for developing effective prevention and treatment methods for neurodegenerative disorders. • This paper reviews the role of lipid metabolism in the occurrence and development of Alzheimer's disease and Parkinson's disease and demonstrates the potential of developing relevant therapeutic strategies based on lipid metabolism as a breakthrough point. • We updated the mechanisms of the involvement of lipid metabolism in the pathogenesis of AD and PD and clarified the theoretical basis of the involvement of lipid metabolism in disease. • This paper reviews the application of lipid monitoring in AD and PD. • In this paper, we summarize the current treatment methods and the latest research progress for specific lipid metabolism pathways and confirm the possibility of clinical treatment. [ABSTRACT FROM AUTHOR]

Neurons are basic units of our nervous system used for communication between the brain and the body. Any disruption in their structures or communication can result in several disorders like Dementia and Alzheimer's disease (A.D.). In this paper, we explore the alterations in neurons causing A.D. Due to specific genetic mutations, neurons release and accumulate tau protein and beta-amyloid protein, thus hampering the communication process, leading to neuron death known as brain atrophy, and eventually shrinking the brain is the case in A.D. This paper discusses neuron modeling of a typical neuron and an Alzheimer's neuron to understand the difference and progression of A.D. and the fact that once these equations are concluded, they could be used to control the brain through a brain-computer interface. Modeling of neurons enables exploring different parameters and understanding the behavior of a particular system, and finally, concluding to represent a biological activity mathematically. [ABSTRACT FROM AUTHOR]

Objectives: With the development of new technologies capable of detecting low concentrations of Alzheimer's disease (AD) relevant biomarkers, the idea of a blood-based diagnosis of AD is nearing reality. This study aims to consider the evidence of total and phosphorylated tau as blood-based biomarkers for mild cognitive impairment (MCI) and AD when compared to healthy controls. Methods: Studies published between 1 January 2012 and 1 May 2021 (Embase and MEDLINE databases) measuring plasma/serum levels of tau in AD, MCI, and control cohorts were screened for eligibility, including quality and bias assessment via a modified QUADAS. The meta-analyses comprised 48 studies assessing total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and tau phosphorylated at threonine 217 (p-tau217), comparing the ratio of biomarker concentrations in MCI, AD, and cognitively unimpaired (CU) controls. Results: Plasma/serum p-tau181 (mean effect size, 95% CI, 2.02 (1.76–2.27)) and t-tau (mean effect size, 95% CI, 1.77 (1.49–2.04)) were elevated in AD study participants compared to controls. Plasma/serum p-tau181 (mean effect size, 95% CI, 1.34 (1.20–1.49)) and t-tau (mean effect size, 95% CI, 1.47 (1.26–1.67)) were also elevated with moderate effect size in MCI study participants compared to controls. p-tau217 was also assessed, albeit in a small number of eligible studies, for AD vs. CU (mean effect size, 95% CI, 1.89 (1.86–1.92)) and for MCI vs. CU groups (mean effect size, 95% CI, 4.16 (3.61–4.71)). Conclusions: This paper highlights the growing evidence that blood-based tau biomarkers have early diagnostic utility for Alzheimer's disease. Registration: PROSPERO No. CRD42020209482. [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]

Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease‐modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker‐based guidelines for AD diagnosis, which have replaced the historical symptom‐based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population‐based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost‐effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid‐based biomarkers, with a particular emphasis on those with potential to be translated into blood‐based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p‐tau; T) show particular potential for translation into clinical practice. However, p‐tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non‐AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre‐analytical protocols. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented. [ABSTRACT FROM AUTHOR]

This paper describes a novel approach of detecting different stages of Alzheimer’s disease (AD) and imaging beta-amyloid plaques and tau tangles in the brain using RF sensors. Dielectric measurements were obtained from grey matter and white matter regions of brain tissues with severe AD pathology at a frequency range of 200 MHz to 3 GHz using a vector network analyzer and dielectric probe. Computational models were created on CST Microwave Suite using a realistic head model and the measured dielectric properties to represent affected brain regions at different stages of AD. Simulations were carried out to test the performance of the RF sensors. Experiments were performed using textile-based RF sensors on fabricated phantoms, representing a human brain with different volumes of AD-affected brain tissues. Experimental data was collected from the sensors and processed in an imaging algorithm to reconstruct images of the affected areas in the brain. Measured dielectric properties in brain tissues with AD pathology were found to be different from healthy human brain tissues. Simulation and experimental results indicated a correlated shift in the captured reflection coefficient data from RF sensors as the amount of affected brain regions increased. Finally, images reconstructed from the imaging algorithm successfully highlighted areas of the brain affected by plaques and tangles as a result of AD. The results from this study show that RF sensing can be used to identify areas of the brain affected by AD pathology. This provides a promising new non-invasive technique for monitoring the progression of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a leading cause of age-related dementia worldwide. Despite more than a century of intensive research, we are not anywhere near the discovery of a cure for this disease or a way to prevent its progression. Among the various molecular mechanisms proposed for the description of the pathogenesis and progression of AD, the amyloid cascade hypothesis, according to which accumulation of a product of amyloid precursor protein (APP) cleavage, amyloid β (Aβ) peptide, induces pathological changes in the brain observed in AD, occupies a unique niche. Although multiple proteins have been implicated in this amyloid cascade signaling pathway, their structure–function relationships are mostly unexplored. However, it is known that two major proteins related to AD pathology, Aβ peptide, and microtubule-associated protein tau belong to the category of intrinsically disordered proteins (IDPs), which are the functionally important proteins characterized by a lack of fixed, ordered three-dimensional structure. IDPs and intrinsically disordered protein regions (IDPRs) play numerous vital roles in various cellular processes, such as signaling, cell cycle regulation, macromolecular recognition, and promiscuous binding. However, the deregulation and misfolding of IDPs may lead to disturbed signaling, interactions, and disease pathogenesis. Often, molecular recognition-related IDPs/IDPRs undergo disorder-to-order transition upon binding to their biological partners and contain specific disorder-based binding motifs, known as molecular recognition features (MoRFs). Knowing the intrinsic disorder status and disorder-based functionality of proteins associated with amyloid cascade signaling pathway may help to untangle the mechanisms of AD pathogenesis and help identify therapeutic targets. In this paper, we have used multiple computational tools to evaluate the presence of intrinsic disorder and MoRFs in 27 proteins potentially relevant to the amyloid cascade signaling pathway. Among these, BIN1, APP, APOE, PICALM, PSEN1 and CD33 were found to be highly disordered. Furthermore, their disorder-based binding regions and associated short linear motifs have also been identified. These findings represent important foundation for the future research, and experimental characterization of disordered regions in these proteins is required to better understand their roles in AD pathogenesis. [ABSTRACT FROM AUTHOR]

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [18F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [11C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [11C]-TKF can be made by reaction precursor with [11C]MeOTf or 11CH3I, but [11C]MeOTf will give us higher labeling yields and specific activity. [11C]-TKF presented better brain uptake in normal mouse than [18F]-THK523 (3.23% ± 1.25% ID.g-1 vs. 2.62% ± 0.39% ID.g-1 at 2 min post-injection). The acute toxicity studies of [11C]-TKF were unremarkable. [ABSTRACT FROM AUTHOR]

Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer's disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by ß-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 µM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the ß-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE-/-) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD. [ABSTRACT FROM AUTHOR]

Introduction: Dementia is a group of disorders that causes dysfunctions in human cognitive and operating functions. Currently, it is not possible to conduct a fast, low-invasive dementia diagnostic process with the use of peripheral blood biomarkers, however, there is a great deal of research in progress covering this subject. Research on dementia biomarkers in serum validates anticipated health and economic benefits from early screening tests. Biomarkers are also essential for improving the process of developing new drugs. Methods: The result analysis, of current studies on selected biomarker concentrations (Aβ40, Aβ42, t-tau, and YKL-40) and their combination in the serum of patients with dementia and mild cognitive disorders, involved a search for papers available in Medline, PubMed, and Web of Science databases published from 2000 to 2020. Results: The results of conducted cross-sectional studies comparing Aβ40, Aβ42, and Aβ42/Aβ40 among people with cognitive disorders and a control group are incoherent. Most of the analyzed papers showed an increase in t-tau concentration in diagnosed Alzheimer's disease (AD) patients' serum, whereas results of mild cognitive impairment (MCI) groups did not differ from the control groups. In several papers on the concentration of YKL-40 and t-tau/Aβ42 ratio, the results were promising. To date, several studies have only covered the field of biomarker concentrations in dementia disorders other than AD. Conclusions: Insufficient amyloid marker test repeatability may result either from imperfection of the used laboratorial techniques or inadequate selection of control groups with their comorbidities. On the basis of current knowledge, t-tau, t-tau/Aβ42, and YKL-40 seem to be promising candidates as biomarkers of cognitive disorders in serum. YKL-40 seems to be a more useful biomarker in early MCI diagnostics, whereas t-tau can be used as a marker of progress of prodromal states in mild AD. Due to the insignificant number of studies conducted to date among patients with dementia disorders other than AD, it is not possible to make a sound assessment of their usefulness in dementia differential diagnostics. [ABSTRACT FROM AUTHOR]

Human Tau protein is the most reliable biomarker for the prediction of Alzheimer's disease (AD). However, the assay to detect low concentrations of tau protein in serum is a great challenge for the early diagnosis of AD. This paper reports an electrochemiluminescence (ECL) immunosensor for Tau protein in serum samples. Gold nanostars (AuNSs) decorated on carbon nitride nanosheets (AuNS@g-CN nanostructure) show highly strong and stable ECL activity compared to pristine CN nanosheets due to the electrocatalytic and surface plasmon effects of AuNSs. As a result of the strong electromagnetic field at branches, AuNSs showed a better ECL enhancement effect than their spherical counterpart. For the fabrication of a specific immunosensor, immobilized AuNSs were functionalized with a monoclonal antibody specific for Tau protein. In the presence of Tau protein, the ECL intensity of the immunosensor decreased considerably. Under the optimal conditions, this ECL based immunosensor exhibits a dynamic linear range from 0.1 to 100 ng mL−1 with a low limit of detection of 0.034 ng mL−1. The LOD is less than the Tau level in human serum; thus, this study provides a useful method for the determination of Tau. The fabricated ECL immunosensor was successfully applied to the detection of Tau, the biomarker in serum samples. Therefore, the present approach is very promising for application in diagnosing AD within the early stages of the disease. [ABSTRACT FROM AUTHOR]

Background: Acute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer's disease (AD). Methods: This paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers. Results: While the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET. Conclusions: Some proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and the associated neurodegenerative dementia have become of increasing concern in healthcare. The tau protein has been considered a key hallmark of progressive neurodegeneration. In this paper, a large-scale analysis of five datasets (more than 2500 people) from the Global Alzheimer's Association Interactive Network (GAAIN) databases was performed to investigate the association between the level of tau protein, including total tau and phosphorylated tau (p-tau), in cerebrospinal fluid (CSF) and cognitive status. Statistically significant (or marginally significant) high total tau or p-tau concentrations in CSF were observed in dementia patients compared with healthy people in all datasets. There is also a statistically significant (or marginally significant) negative correlation between p-tau concentrations in CSF and Folstein Mini-Mental State Examination (MMSE) scores. In addition, transcriptomic data derived from mouse microglial cells showed multiple genes upregulated in Toll-like receptor signaling and Alzheimer's disease pathways, including TNF, TLR2, IL-1β, and COX subunits, suggesting that the mechanism of action that relates p-tau and MMSE scores may be through overactivation of pro-inflammatory microglial activity by Aβ peptides, TNF-mediated hyperphosphorylation of tau, and the infectious spread of pathological tau across healthy neurons. Our results not only confirmed the association between tau protein level and cognitive status in a large population but also provided useful information for the understanding of the role of tau in neurodegeneration and the development of dementia. [ABSTRACT FROM AUTHOR]

Currently, there is no cure for Alzheimer's disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A β peptides that regulate several key physiological brain processes, and the incomplete understanding of AD′s aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human. [ABSTRACT FROM AUTHOR]

In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer's disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick's disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick's disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease that accounts for 70% of all dementia. Early stage diagnosis of AD is essential as there is no certain treatment after the lesion has progressed in the late stage. Nevertheless, there are still limitations of early diagnosis of AD using neuroimaging and psychological memory assessments. Here, we demonstrate ultrasensitive and multiplexed detection of pivotal AD biomarkers (Aβ 1-42 and t-Tau) in biofluids using a reduced graphene oxide field-effect transistor (gFET). The proposed approach provides a wide logarithmically linear range of detection from 10−1–105 pg mL−1 and a femtomolar-level limit of detection in biofluids (human plasma and artificial cerebrospinal fluid) as well as phosphate-buffered saline (PBS). Furthermore, as these core biomarkers have different surface charges in physiological conditions based on the isoelectric point (pI), we achieved a distinctive output signal for each biomarker. The gFET biosensor platform presented in this paper has great potential and can be used for early diagnosis of AD in clinical practice as well as accurate analysis based on the surface charge of the analytes. • The amyloid-β (Aβ) and tau protein in biofluids are pivotal biomarkers for the early stage diagnosis of Alzheimer's disease. • A graphene-based field-effect transistor (gFET) is designed for multiplexed detection of Aβ 1-42 and total tau (t-Tau). • Aβ 1-42 and t-Tau possess different charges owing to their isoelectric point, resulting in distinctive doping effects on gFET. • Femtomolar detection of Aβ 1-42 and total tau (t-Tau) have been achieved in human plasma and artificial cerebrospinal fluid. [ABSTRACT FROM AUTHOR]