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Search Results (513)

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19 pages, 1461 KiB  
Review
Roles of Type 10 17β-Hydroxysteroid Dehydrogenase in Health and Disease
by Xue-Ying He, Janusz Frackowiak and Song-Yu Yang
J. Pers. Med. 2025, 15(8), 346; https://doi.org/10.3390/jpm15080346 (registering DOI) - 1 Aug 2025
Viewed by 33
Abstract
Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain [...] Read more.
Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported km value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure km. Regarding any reported “one-site competitive inhibition” of ABAD/ERAB by Aβ, the kivalue estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that “ABAD” mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer’s disease. Full article
42 pages, 2457 KiB  
Review
Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review
by Purnima Rani Debi, Hrishika Barua, Mirja Kaizer Ahmmed and Shuva Bhowmik
Mar. Drugs 2025, 23(8), 310; https://doi.org/10.3390/md23080310 - 30 Jul 2025
Viewed by 147
Abstract
The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being [...] Read more.
The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer’s disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders. Full article
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30 pages, 3414 KiB  
Article
In Vitro Neuroprotective Effects of a Mixed Extract of Bilberry, Centella asiatica, Hericium erinaceus, and Palmitoylethanolamide
by Rebecca Galla, Sara Ferrari, Ivana Miletto, Simone Mulè and Francesca Uberti
Foods 2025, 14(15), 2678; https://doi.org/10.3390/foods14152678 - 30 Jul 2025
Viewed by 284
Abstract
Oxidative stress, driven by impaired antioxidant defence systems, is a major contributor to cognitive decline and neurodegenerative processes in brain ageing. This study investigates the neuroprotective effects of a natural compound mixture—composed of Hericium erinaceus, Palmitoylethanolamide, Bilberry extract, and Centella asiatica—using [...] Read more.
Oxidative stress, driven by impaired antioxidant defence systems, is a major contributor to cognitive decline and neurodegenerative processes in brain ageing. This study investigates the neuroprotective effects of a natural compound mixture—composed of Hericium erinaceus, Palmitoylethanolamide, Bilberry extract, and Centella asiatica—using a multi-step in vitro strategy. An initial evaluation in a 3D intestinal epithelial model demonstrated that the formulation preserves barrier integrity and may be bioaccessible, as evidenced by transepithelial electrical resistance (TEER) and the expression of tight junctions. Subsequent analysis in an integrated gut–brain axis model under oxidative stress conditions revealed that the formulation significantly reduces inflammatory markers (NF-κB, TNF-α, IL-1β, and IL-6; about 1.5-fold vs. H2O2), reactive oxygen species (about 2-fold vs. H2O2), and nitric oxide levels (about 1.2-fold vs. H2O2). Additionally, it enhances mitochondrial activity while also improving antioxidant responses. In a co-culture of neuronal and astrocytic cells, the combination upregulates neurotrophic factors such as BDNF and NGF (about 2.3-fold and 1.9-fold vs. H2O2). Crucially, the formulation also modulates key biomarkers associated with cognitive decline, reducing APP and phosphorylated tau levels (about 98% and 1.6-fold vs. H2O2) while increasing Sirtuin 1 and Nrf2 expression (about 3.6-fold and 3-fold vs. H2O2). These findings suggest that this nutraceutical combination may support the cellular pathways involved in neuronal resilience and healthy brain ageing, offering potential as a functional food ingredient or dietary supplement. Full article
(This article belongs to the Section Food Nutrition)
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30 pages, 1032 KiB  
Review
Circulating Biomarkers for the Early Diagnosis of Alzheimer’s Disease
by Vharoon Sharma Nunkoo, Anamaria Jurcau, Mihaela Les, Alexander Cristian, Marius Militaru, Cristian Marge, Diana Carina Iovanovici and Maria Carolina Jurcau
Int. J. Mol. Sci. 2025, 26(15), 7268; https://doi.org/10.3390/ijms26157268 - 27 Jul 2025
Viewed by 518
Abstract
With a rapidly growing incidence and prevalence, Alzheimer’s disease (AD) is rapidly becoming one of the most disabling, lethal, and expensive diseases of the century. To diagnose AD as early as possible, the scientific world struggles to find reliable and non-invasive biomarkers that [...] Read more.
With a rapidly growing incidence and prevalence, Alzheimer’s disease (AD) is rapidly becoming one of the most disabling, lethal, and expensive diseases of the century. To diagnose AD as early as possible, the scientific world struggles to find reliable and non-invasive biomarkers that could predict the conversion of mild cognitive impairment to AD and delineate the ongoing pathogenic vicious pathways to be targeted with therapy. Research supports the use of blood biomarkers, such as Aβ1-42/Aβ1-40 ratio, phosphorylated tau181, and p-tau217 for diagnostic purposes, although the cut-offs are not clearly established and can depend on the assays used. For more accurate diagnosis, markers of neurodegeneration (neurofilament light) and neuroinflammation (glial fibrillary acidic protein) could be introduced in the biomarker panel. The recent approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio by the FDA for the early detection of amyloid plaques associated with Alzheimer’s disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease represents a significant advancement in the diagnosis of Alzheimer’s disease, offering a more accessible and less invasive way to diagnose this devastating disease and allow potentially earlier access to treatment options. Full article
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17 pages, 810 KiB  
Article
Association Analysis Between Ischemic Stroke Risk Single Nucleotide Polymorphisms and Alzheimer’s Disease
by Wei Dong, Wei Wang and Mingxuan Li
Bioengineering 2025, 12(8), 804; https://doi.org/10.3390/bioengineering12080804 - 26 Jul 2025
Viewed by 233
Abstract
Alzheimer’s disease (AD) and ischemic stroke (IS) are prevalent neurological disorders that frequently co-occur in the same individuals. Recent studies have demonstrated that AD and IS share several common risk factors and pathogenic elements, including an overlapping genomic architecture. However, the relationship between [...] Read more.
Alzheimer’s disease (AD) and ischemic stroke (IS) are prevalent neurological disorders that frequently co-occur in the same individuals. Recent studies have demonstrated that AD and IS share several common risk factors and pathogenic elements, including an overlapping genomic architecture. However, the relationship between IS risk gene polymorphisms and AD has been less extensively studied. We aimed at determining whether IS risk gene polymorphisms were associated with the risk of AD and the severity of AD in AD patients. We utilized data of AD patients and normal controls (NCs) sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. IS risk single nucleotide polymorphisms (SNPs) were identified through the most recent and largest IS genome-wide association study (GWAS) meta-analysis. Subsequently, we conducted SNP-based association analysis of IS-risk SNPs with the risk of AD, along with amyloid, tau, and neuroimaging for AD. The generalized multifactor dimensionality reduction (GMDR) model was used to assess the interactions among IS-risk SNPs and apolipoprotein E (ApoE) ε4. Protein–protein interactions (PPIs) of the IS-risk genes product and APOE were explored using the STRING database. Seven IS-risk SNPs were involved in the study. Five SNPs were found to be associated with at least one measurement of cerebrospinal fluid (CSF) levels of amyloid-beta 1–42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau181), as well as the volumes of the hippocampus, whole brain, entorhinal cortex, and mid-temporal regions. After multiple testing corrections, we found that T allele of rs1487504 contributed to an increased risk of AD in non-ApoE ε4 carriers. The combination of rs1487504 and ApoE ε4 emerged as the optimal two-factor model, and its interaction was significantly related to the risk of AD. Additionally, C allele of rs880315 was significantly associated with elevated levels of CSF Aβ42 in AD patients, and A allele of rs10774625 was significantly related to a reduction in the volume of the entorhinal cortex in AD patients. This study found that IS risk SNPs were associated with both the risk of AD and AD major indicators in the ADNI cohort. These findings elucidated the role of IS in AD from a genetic perspective and provided an innovative approach to predict AD through IS-risk SNPs. Full article
(This article belongs to the Section Biomedical Engineering and Biomaterials)
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12 pages, 462 KiB  
Article
AI-Based Classification of Mild Cognitive Impairment and Cognitively Normal Patients
by Rafail Christodoulou, Giorgos Christofi, Rafael Pitsillos, Reina Ibrahim, Platon Papageorgiou, Sokratis G. Papageorgiou, Evros Vassiliou and Michalis F. Georgiou
J. Clin. Med. 2025, 14(15), 5261; https://doi.org/10.3390/jcm14155261 - 25 Jul 2025
Viewed by 366
Abstract
Background: Mild Cognitive Impairment (MCI) represents an intermediate stage between normal cognitive aging and Alzheimer’s Disease (AD). Early and accurate identification of MCI is crucial for implementing interventions that may delay or prevent further cognitive decline. This study aims to develop a [...] Read more.
Background: Mild Cognitive Impairment (MCI) represents an intermediate stage between normal cognitive aging and Alzheimer’s Disease (AD). Early and accurate identification of MCI is crucial for implementing interventions that may delay or prevent further cognitive decline. This study aims to develop a machine learning-based model for differentiating between Cognitively Normal (CN) individuals and MCI patients using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods: An ensemble classification approach was designed by integrating Extra Trees, Random Forest, and Light Gradient Boosting Machine (LightGBM) algorithms. Feature selection emphasized clinically relevant biomarkers, including Amyloid-β 42, phosphorylated tau, diastolic blood pressure, age, and gender. The dataset was split into training and held-out test sets. A probability thresholding strategy was employed to flag uncertain predictions for potential deferral, enhancing model reliability in borderline cases. Results: The final ensemble model achieved an accuracy of 83.2%, a recall of 80.2%, and a precision of 86.3% on the independent test set. The probability thresholding mechanism flagged 23.3% of cases as uncertain, allowing the system to abstain from low-confidence predictions. This strategy improved clinical interpretability and minimized the risk of misclassification in ambiguous cases. Conclusions: The proposed AI-driven ensemble model demonstrates strong performance in classifying MCI versus CN individuals using multimodal ADNI data. Incorporating a deferral mechanism through uncertainty estimation further enhances the model’s clinical utility. These findings support the integration of machine learning tools into early screening workflows for cognitive impairment. Full article
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33 pages, 8117 KiB  
Article
Induced Microglial-like Cells Derived from Familial and Sporadic Alzheimer’s Disease Peripheral Blood Monocytes Show Abnormal Phagocytosis and Inflammatory Response to PSEN1 E280A Cholinergic-like Neurons
by Viviana Soto-Mercado, Miguel Mendivil-Perez, Carlos Velez-Pardo and Marlene Jimenez-Del-Rio
Int. J. Mol. Sci. 2025, 26(15), 7162; https://doi.org/10.3390/ijms26157162 - 24 Jul 2025
Viewed by 355
Abstract
In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in [...] Read more.
In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca2+ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca2+ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article
(This article belongs to the Special Issue Role of Glia in Human Health and Disease)
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14 pages, 1664 KiB  
Article
Depletion of IGFALS Serum Level up to 3 Months After Cardiac Surgery, with Exploration of Potential Relationships to Surrogates of Organ Failures and Clinical Outcomes
by Krzysztof Laudanski, Mohamed A. Mahmoud, Hossam Gad and Daniel A. Diedrich
Curr. Issues Mol. Biol. 2025, 47(8), 581; https://doi.org/10.3390/cimb47080581 - 23 Jul 2025
Viewed by 205
Abstract
The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients [...] Read more.
The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients undergoing elective cardiac surgery with implementation of cardiopulmonary bypass had their serum isolated at baseline, 24 h, seven days, and three months postoperatively to assess serum concentrations of IGFALS and insulin growth factor 1 (IGF-1). Markers of perioperative injury included troponin I (TnI), high-mobility group box 1 (HMGB-1), and heat shock protein 60 (Hsp-60). Inflammatory status was assessed via interleukin-6 (IL-6) and interleukin-8 (IL-8). Additionally, we measured in vitro cytokine production to viral stimulation of whole blood and monocytes. Surrogates of neuronal distress included neurofilament light chain (NF-L), total tau (τ), phosphorylated tau at threonine 181 (τp181), and amyloid β40 and β42. Renal impairment was defined by RIFLE criteria. Cardiac dysfunction was denoted by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Serum IGFALS levels declined significantly after surgery and remained depressed even at 3 months. Administration of acetaminophen and acetylsalicylic acid differentiated IGFALS levels at the 24 h postoperatively. Serum IGFALS 24 h post-operatively correlated with production of cytokines by leukocytes after in vitro viral stimulation. Serum amyloid-β1-42 was significantly associated with IGFALS at baseline and 24 h post-surgery Patients discharged home had higher IGFALS levels at 28 days and 3 months than those discharged to healthcare facilities or who died. These findings suggest that IGFALS may serve as a prognostic biomarker for recovery trajectory and postoperative outcomes in cardiac surgery patients. Full article
(This article belongs to the Special Issue The Role of Neuroinflammation in Neurodegenerative Diseases)
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35 pages, 1902 KiB  
Review
From Amyloid to Synaptic Dysfunction: Biomarker-Driven Insights into Alzheimer’s Disease
by Luisa Agnello, Caterina Maria Gambino, Anna Maria Ciaccio, Francesco Cacciabaudo, Davide Massa, Anna Masucci, Martina Tamburello, Roberta Vassallo, Mauro Midiri, Concetta Scazzone and Marcello Ciaccio
Curr. Issues Mol. Biol. 2025, 47(8), 580; https://doi.org/10.3390/cimb47080580 - 22 Jul 2025
Viewed by 383
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and represents a major public health challenge. With increasing life expectancy, the incidence of AD has also increased, highlighting the need for early diagnosis and improved monitoring. Traditionally, diagnosis has relied on clinical symptoms [...] Read more.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and represents a major public health challenge. With increasing life expectancy, the incidence of AD has also increased, highlighting the need for early diagnosis and improved monitoring. Traditionally, diagnosis has relied on clinical symptoms and neuroimaging; however, the introduction of biomarkers has revolutionized disease assessment. Traditional biomarkers, including the Aβ42/Aβ40 ratio, phosphorylated tau (p-Tau181, p-Tau217, and p-Tau231), total tau (t-tau), and neurofilament light chain (NfL), are fundamental for staging AD progression. Updated guidelines introduced the ATX(N) model, which extends biomarker classification to include additional promising biomarkers, such as SNAP-25, YKL-40, GAP-43, VILIP-1, progranulin (PGRN), TREM2, IGF-1, hFABP, MCP-1, TDP-43, and BDNF. Recent advancements have allowed for the detection of these biomarkers not only in CSF but also in plasma and neuron-derived exosomes, offering less invasive and more accessible diagnostic options. This review explores established and emerging biomarkers and emphasizes their roles in early diagnosis, patient stratification, and precision medicine. Full article
(This article belongs to the Section Molecular Medicine)
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18 pages, 4051 KiB  
Article
Change in Mechanical Property of Rat Brain Suffering from Chronic High Intraocular Pressure
by Yukai Zeng, Kunya Zhang, Zhengyuan Ma and Xiuqing Qian
Bioengineering 2025, 12(8), 787; https://doi.org/10.3390/bioengineering12080787 - 22 Jul 2025
Viewed by 257
Abstract
Glaucoma is a trans-synaptic neurodegenerative disease, and the pathological increase in intraocular pressure (IOP) is a major risk factor of glaucoma. High IOP alters microstructure and morphologies of the brain tissue. Since mechanical properties of the brain are sensitive to the alteration of [...] Read more.
Glaucoma is a trans-synaptic neurodegenerative disease, and the pathological increase in intraocular pressure (IOP) is a major risk factor of glaucoma. High IOP alters microstructure and morphologies of the brain tissue. Since mechanical properties of the brain are sensitive to the alteration of the tissue microstructure, we investigate how varying durations of chronic elevated IOP alter brain mechanical properties. A chronic high IOP rat model was induced by episcleral vein cauterization with subconjunctival injection of 5-Fluorouracil. At 2, 4 and 8 weeks after induction, indentation tests were performed on the brain slices to measure mechanical properties in the hippocampus, lateral geniculate nucleus and occipital lobe of both hemispheres. Meanwhile, the brain’s microstructure was assessed via F-actin and myelin staining. Compared to the blank control group, the Young’s modulus decreased in all three brain regions in the highIOP experimental groups. F-actin fluorescence intensity and myelin area fraction were reduced in the hippocampus, while β-amyloid levels and tau phosphorylation were elevated in the experimental groups. Our study provides insight into Alzheimer’s disease pathogenesis by demonstrating how chronic high IOP alters the brain’s mechanical properties. Full article
(This article belongs to the Special Issue Bioengineering Strategies for Ophthalmic Diseases)
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16 pages, 2462 KiB  
Article
Performance of Plasma Phosphorylated tau-217 in Patients on the Continuum of Alzheimer’s Disease
by Farida Dakterzada, Ricard López-Ortega, Alba Vilella-Figuerola, Nathalia Montero-Castilla, Iolanda Riba-Llena, Maria Ruiz-Julián, Alfonso Arias, Jordi Sarto, Nuria Tahan and Gerard Piñol-Ripoll
Int. J. Mol. Sci. 2025, 26(14), 6771; https://doi.org/10.3390/ijms26146771 - 15 Jul 2025
Viewed by 381
Abstract
Recent studies have demonstrated the high analytical and diagnostic performance of plasma p-tau217 using well-defined cohorts. We aimed to assess the analytical, diagnostic, and prognostic utility of plasma p-tau217 as a routine biomarker in symptomatic patients attending our memory clinic. We also sought [...] Read more.
Recent studies have demonstrated the high analytical and diagnostic performance of plasma p-tau217 using well-defined cohorts. We aimed to assess the analytical, diagnostic, and prognostic utility of plasma p-tau217 as a routine biomarker in symptomatic patients attending our memory clinic. We also sought to identify optimal cutoff points that align with cerebrospinal fluid (CSF) amyloid beta (Aβ) status. A total of 276 cognitively impaired patients were included, with 81 mild cognitive impairment (MCI) patients followed for a mean of 56 (±15.8) months to evaluate progression to Alzheimer’s disease (AD). CSF and blood biomarkers of AD were quantified using the Lumipulse G platform. Plasma p-tau217 levels showed strong correlations with CSF Aβ42/Aβ40 (r = −0.707), p-tau181/Aβ42 (r = 0.842), and p-tau181 (r = 0.728). Plasma p-tau217 levels were significantly higher in the A + T + group than in A − T +/− (p < 0.001) and outperformed other plasma markers in detecting CSF Aβ pathology (AUC 0.924).Additionally, p-tau217 moderated cognitive changes over time as measured by the Mini-mental state examination (MMSE) (F(2, 70) = 13.995, p < 0.001) and outperformed other plasma biomarkers in predicting progression from MCI to AD (AUC 0.876). Using a dual cutoff strategy, 72% of patients were classified with 94.9% concordance with CSF Aβ status. Plasma p-tau217 shows strong potential as a non-invasive, cost-effective diagnostic and prognostic tool in clinical settings. Full article
(This article belongs to the Special Issue Biomarkers in Precision Medicine)
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15 pages, 1466 KiB  
Article
Effect of Tau Fragment and Membrane Interactions on Membrane Permeabilization and Peptide Aggregation
by Majedul Islam, Md Raza Ul Karim, Emily Argueta, Mohammed N. Selim, Ewa P. Wojcikiewicz and Deguo Du
Membranes 2025, 15(7), 208; https://doi.org/10.3390/membranes15070208 - 13 Jul 2025
Viewed by 1072
Abstract
Aggregation of tau protein is a hallmark feature of tauopathies such as Alzheimer’s disease. The microtubule-binding domain of tau plays a crucial role in the tau aggregation process. In this study, we investigated the dual effects of membrane interactions of tau298–317, [...] Read more.
Aggregation of tau protein is a hallmark feature of tauopathies such as Alzheimer’s disease. The microtubule-binding domain of tau plays a crucial role in the tau aggregation process. In this study, we investigated the dual effects of membrane interactions of tau298–317, a fragment peptide from the microtubule-binding domain, on peptide-induced membrane disruption and membrane-mediated peptide self-assembly. Our results show that neither wild-type tau298–317 nor its P301L or Ser305-phosphorylated mutants aggregate in the presence of zwitterionic POPC vesicles or cause lipid vesicle leakage, indicating weak peptide–membrane interactions. In contrast, tau298–317 strongly interacts with negatively charged POPG liposomes, leading to a rapid transition of the peptide conformation from random coils to α-helical intermediate conformation upon membrane adsorption, which may further promote peptide self-association to form oligomers and β-sheet-rich fibrillar structures. Tau298–317-induced rapid POPG membrane leakage indicates a synergistic process of the peptide self-assembly at the membrane interface and the aggregation-induced membrane disruption. Notably, phosphorylation at Ser305 disrupts favorable electrostatic interactions between the peptide and POPG membrane surface, thus preventing peptide aggregation and membrane leakage. In contrast, the P301L mutation significantly enhances membrane-mediated peptide aggregation and peptide-induced membrane disruption, likely due to alleviation of local conformational constraints and enhancement of local hydrophobicity, which facilitates fast conformational conversion to β-sheet structures. These findings provide mechanistic insights into the molecular mechanisms underlying membrane-mediated aggregation of crucial regions of tau and peptide-induced membrane damage, indicating potential strategies to prevent tau aggregation and membrane rupture by targeting critical electrostatic interactions between membranes and key local regions of tau. Full article
(This article belongs to the Section Biological Membranes)
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21 pages, 4391 KiB  
Article
Thermal Cycling-Hyperthermia Attenuates Rotenone-Induced Cell Injury in SH-SY5Y Cells Through Heat-Activated Mechanisms
by Yu-Yi Kuo, Guan-Bo Lin, You-Ming Chen, Hsu-Hsiang Liu, Fang-Tzu Hsu, Yi Kung and Chih-Yu Chao
Int. J. Mol. Sci. 2025, 26(14), 6671; https://doi.org/10.3390/ijms26146671 - 11 Jul 2025
Viewed by 358
Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by mitochondrial dysfunction, increased reactive oxygen species (ROS), α-synuclein (α-syn) and phosphorylated-tau protein (p-tau) aggregation, and dopaminergic neuron cell death. Current drug therapies only provide temporary symptomatic relief and fail [...] Read more.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by mitochondrial dysfunction, increased reactive oxygen species (ROS), α-synuclein (α-syn) and phosphorylated-tau protein (p-tau) aggregation, and dopaminergic neuron cell death. Current drug therapies only provide temporary symptomatic relief and fail to stop or reverse disease progression due to the severe side effects or the blood–brain barrier. This study aimed to investigate the neuroprotective effects of an intermittent heating approach, thermal cycling-hyperthermia (TC-HT), in an in vitro PD model using rotenone (ROT)-induced human neural SH-SY5Y cells. Our results revealed that TC-HT pretreatment conferred neuroprotective effects in the ROT-induced in vitro PD model using human SH-SY5Y neuronal cells, including reducing ROT-induced mitochondrial apoptosis and ROS accumulation in SH-SY5Y cells. In addition, TC-HT also inhibited the expression of α-syn and p-tau through heat-activated pathways associated with sirtuin 1 (SIRT1) and heat-shock protein 70 (Hsp70), involved in protein chaperoning, and resulted in the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), which inhibit p-tau formation. These findings underscore the potential of TC-HT as an effective treatment for PD in vitro, supporting its further investigation in in vivo models with focused ultrasound (FUS) as a feasible heat-delivery approach. Full article
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17 pages, 937 KiB  
Review
P-tau217 as a Biomarker in Alzheimer’s Disease: Applications in Latin American Populations
by Christian Alexis Varela-Vidales, Alejandra Martínez-Hernández, Elizabeth Hernández-Castellanos and Daniela L. C. Delgado-Lara
Int. J. Mol. Sci. 2025, 26(14), 6633; https://doi.org/10.3390/ijms26146633 - 10 Jul 2025
Viewed by 535
Abstract
Alzheimer’s disease (AD) is one of the primary dementia causes worldwide. For this reason, there is a need for plasma-based diagnostic biomarkers to facilitate the timely diagnosis of AD. This work synthesizes the current evidence concerning the tau protein p-tau phosphorylated at threonine [...] Read more.
Alzheimer’s disease (AD) is one of the primary dementia causes worldwide. For this reason, there is a need for plasma-based diagnostic biomarkers to facilitate the timely diagnosis of AD. This work synthesizes the current evidence concerning the tau protein p-tau phosphorylated at threonine 217 (p-tau217) as an emerging biomarker, emphasizing its utility in preclinical phases and its potential application in Latin American populations. The findings indicate that p-tau217 has superior sensitivity and specificity compared to classical biomarkers such as p-tau181 and Aβ42. Likewise, its plasma concentration regulates neuropathological progression, as studies by Braak have shown, enabling it to identify alterations from the early stages. In Latin America, studies in Peru, Colombia, and Brazil have shown promising results, albeit with methodological limitations. Some of them have small sample sizes or lack neuroimaging confirmation. Additionally, clinical factors common in the region, such as hypertension, diabetes, or chronic kidney disease, may alter the clinical interpretation. In short, p-tau217 represents a potential non-invasive diagnostic resource. More diverse cohorts are needed to confirm its validity in daily clinical practice. Full article
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18 pages, 3083 KiB  
Article
Hypergravity and ERK Inhibition Combined Synergistically Reduce Pathological Tau Phosphorylation in a Neurodegenerative Cell Model
by Valerio Mignucci, Ivana Barravecchia, Davide De Luca, Giacomo Siano, Cristina Di Primio, Jack J. W. A. van Loon and Debora Angeloni
Cells 2025, 14(14), 1058; https://doi.org/10.3390/cells14141058 - 10 Jul 2025
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Abstract
This study evaluates the effects of hypergravity (HG) on a neurodegenerative model in vitro, looking at how HG influences Tau protein aggregation in Mouse Hippocampal Neuronal Cells (HT22) induced by neurofibrillary tangle seeds. Overall, 50× g significantly, synergistically, reduced the Tau aggregate Area [...] Read more.
This study evaluates the effects of hypergravity (HG) on a neurodegenerative model in vitro, looking at how HG influences Tau protein aggregation in Mouse Hippocampal Neuronal Cells (HT22) induced by neurofibrillary tangle seeds. Overall, 50× g significantly, synergistically, reduced the Tau aggregate Area when combined with ERK-inhibitor PD-0325901, correlating with decreased phosphorylation at critical residues pS262 and pS396. These findings suggest HG treatments may help mitigate cytoskeletal damage linked to Tau aggregation. Full article
(This article belongs to the Special Issue Ageing and Neurodegenerative Diseases, Second Edition)
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