Tau Protein Research Articles

Biomarkers for cognitive impairment in alpha-synucleinopathies: an overview of systematic reviews and meta-analyses

Cognitive impairment (CI) is common in α-synucleinopathies, i.e., Parkinson’s disease, Lewy bodies dementia, and multiple system atrophy. We summarize data from systematic reviews/meta-analyses on neuroimaging, neurophysiology, biofluid and genetic diagnostic/prognostic biomarkers of CI in α-synucleinopathies. Diagnostic biomarkers include atrophy/functional neuroimaging brain changes, abnormal cortical amyloid and tau deposition, and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers, cortical rhythm slowing, reduced cortical cholinergic and glutamatergic and increased cortical GABAergic activity, delayed P300 latency, increased plasma homocysteine and cystatin C and decreased vitamin B12 and folate, increased CSF/serum albumin quotient, and serum neurofilament light chain. Prognostic biomarkers include brain regional atrophy, cortical rhythm slowing, CSF amyloid biomarkers, Val66Met polymorphism, and apolipoprotein-E ε2 and ε4 alleles. Some AD/amyloid/tau biomarkers may diagnose/predict CI in α-synucleinopathies, but single, validated diagnostic/prognostic biomarkers lack. Future studies should include large consortia, biobanks, multi-omics approach, artificial intelligence, and machine learning to better reflect the complexity of CI in α-synucleinopathies.

Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

Relationship of Retroelements with Antiviral Proteins and Epigenetic Factors in Alzheimer's Disease

Genetic factors such as allelic variants of the PSEN1, PSEN2, APP, and APOE genes play an important role in Alzheimer's disease development. Still, they cannot explain all cases of the disease and cannot form the basis for effective treatment methods for the pathology. Alzheimer's disease is the most common neurodegenerative disease, so identifying new mechanisms of pathogenesis may reveal new ways of treating it. Since Alzheimer's disease is associated with aging, the hypothesis is proposed that an important trigger mechanism for it is the pathological activation of retroelements during aging, leading to epigenetic changes. This is due to the role of retroelements in gene expression regulation and the origin of long noncoding RNAs and microRNAs from transposons, changes in the expression of which are observed both during aging and Alzheimer's disease. Normally, activation of retroelements is observed in hippocampal neuronal stem cells, which is necessary for epigenetic programming during neuronal differentiation. Direct changes in the expression of retroelements in Alzheimer's disease have also been described. It has been suggested that aging is a trigger for the development of Alzheimer's disease due to the pathological activation of retroelements. To confirm this hypothesis, an analysis of specific microRNAs associated with Alzheimer's disease and aging in the MDTE DB (microRNAs derived from Transposable elements) database was conducted. As a result, identified expression changes in Alzheimer's disease of 37 individual microRNAs derived from retroelements (25 from LINE, 7 from SINE, 5 from HERV), of which 12 changes expression during physiological aging, which confirms my hypothesis that the activation of retroelements during physiological aging is a driver for Alzheimer's disease. This is evidenced by the defeat of diseases mainly by the elderly and older adults. Since 3 of the 12 miRNAs associated with aging and Alzheimer's disease originated from SINE/MIRs that evolved from tRNAs, the role of tRNAs and the tRFs and tRNA halves derived from them in the development of Alzheimer's disease, which are evolutionarily closely related to retroelements was described. These results are promising for targeted disease therapy in the mechanisms of RNA-directed DNA methylation with possible complex use of retroelement enzyme inhibitors. Additional evidence for the role of retroelements in the development of Alzheimer's disease is that overexpression of tau, which has antiviral properties, with its interaction with beta-amyloid leads to dysregulation of retroelements, and in tauopathies, activation of ERV is determined. At the same time, the effect of retroelements as inducers of proteinopathy and tau aggregation has been described. In addition, HIV and herpes viruses, which affect beta-amyloid and tau protein, are also activators of retroelements. Also, polymorphisms associated with Alzheimer's disease are located mainly in intronic and intergenic regions where retroelements are located, affecting changes in their activity.

Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion.

Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick's disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer's disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.

Pathological study of progressive supranuclear palsy the cases with mutations in Bassoon.

Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP is defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence of neurofibrillary tangles (NFTs) and accumulation of phosphorylated tau protein in neurons and glial cells in the brain. We previously identified the point mutation p.Pro3866Ala in the Bassoon (BSN) gene in a Japanese family with PSP-like syndrome. We newly detected BSN mutations in two autopsied PSP cases carrying p.Thr2542Met and p.Glu2759Gly, respectively. The case with p.Thr2542Met mutation showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, and parkinsonism. Brain magnetic resonance imaging (MRI) showed atrophy of the midbrain tegmentum and hippocampus. Pathologically, moderate to severe loss of neurons with gliosis was also found in the substantia nigra, and there was an almost complete loss of neurons with gliosis in the transitional zone of the cornu ammonis (CA) 1 region to the subiculum. NFTs were observed in the globus pallidus, subthalamic nucleus, substantia nigra, and CA1. 4R tau-dominant tauopathy was detected. The case with p.Glu2759Gly mutation showed neurological symptoms, including right-dominant motor impairment, right limping gait, postural instability, and cognitive dysfunction. Brain MRI showed mild atrophy of the midbrain tegmentum and left-dominant parietal lobe atrophy. Pathologically, NFTs were detected in the globus pallidus, subthalamic nucleus, substantia nigra, thalamus, putamen, and brainstem tegmentum. Most neurons were immunopositive for four-repeat tau, whereas only a few of them harbored three-repeat tau-positive NFTs in the hippocampus. We showed the results of a pathological study of PSP cases with BSN mutations; these were two new cases. The clinical phenotypes were similar to the first case in the point of neurological symptoms. Accumulation of four-repeat tau was dominant. Further autopsies of BSN mutation cases and further elucidation of the molecular biological mechanism are desirable.

Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease

The most prevalent chronic neurodegenerative illness in the world is Alzheimer’s disease (AD). It results in mental symptoms including behavioral abnormalities and cognitive impairment, which have a substantial financial and psychological impact on the relatives of the patients. The review discusses various pathophysiological mechanisms contributing to AD, including amyloid beta, tau protein, inflammation, and other factors, while emphasizing the need for effective disease-modifying therapeutics that alter disease progression rather than merely alleviating symptoms. This review mainly covers medications that are now being studied in clinical trials or recently approved by the FDA that fall under the disease-modifying treatment (DMT) category, which alters the progression of the disease by targeting underlying biological mechanisms rather than merely alleviating symptoms. DMTs focus on improving patient outcomes by slowing cognitive decline, enhancing neuroprotection, and supporting neurogenesis. Additionally, the review covers amyloid-targeting therapies, tau-targeting therapies, neuroprotective therapies, and others. This evaluation specifically looked at studies on FDA-approved novel DMTs in Phase II or III development that were carried out between 2021 and 2024. A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.

SARS-CoV-2 propagation to the TPH2-positive neurons in the ventral tegmental area induces cell death via GSK3β-dependent accumulation of phosphorylated tau.

COVID-19, an infectious disease caused by SARS-CoV-2, was declared a pandemic by the WHO in 2020. Psychiatric symptoms including sleep disturbance, memory impairment, and depression are associated with SARS-CoV-2 infection. These symptoms are causes long-term mental and physical distress in recovering patients; however, the underlying mechanism is unclear. In this study, we determined the effects of SARS-CoV-2 infection on brain tissue using k18hACE2 mice. Using brain tissue from 18hACE2 mice infected with SARS-CoV-2 through intranasal administration, SARS-CoV-2 spike protein and RNA were analyzed by immunohistochemical staining and in-situ hybridization. Immunohistochemical analysis revealed that Tryptophan hydroxylase 2 (TPH2)-positive cells and SARS-CoV-2 spike protein were co-localized in the ventral tegmental area of SARS-CoV-2-infected mice. We observed decreased TPH2 expression and increased accumulation of phosphorylated tau protein and Phospho-Histone H2A.X (γH2AX) expression in the ventral tegmental region. In addition, activation of glycogen synthase kinase 3β (GSK3β) was induced by SARS-CoV-2 infection. Overall, our results suggest that SARS-CoV-2 infection of TPH2-positive cells in the ventral tegmental area induces neuronal cell death through increased accumulation of phosphorylated tau. Attenuation of the GSK3β pathway and decreased serotonin synthesis through suppression of TPH2 expression may contribute to the development of neurological symptoms.

A-β Related Pathogenesis of AD Progress of Its Targeted Therapy

Alzheimer’s disease is a common type of dementia in people 65 years of age and older. Tens of millions of people worldwide are living with AD, and the number continues to grow. To date, there are several hypotheses about the pathogenesis of AD, the most widely studied of which is related to the accumulation of Aβ. Currently, there are five drugs in clinical treatment, most of which are inhibitors, as well as monoclonal antibody drugs such as Aducanumab that target Aβ. These drugs can effectively reduce the accumulation of Aβ. However, these drugs have significant side effects and are generally significantly reduced by the end of AD symptoms. This review will summarize the pathogenesis of AD related to Aβ, such as APP and neuroinflammation. This article will also discuss the progress and problems of existing Aβ-based therapies. In addition, this paper will also compare Aβ and Tau proteins to explore better AD treatment methods. These are the basis for further study of the pathogenesis of AD related to Aβ and the development of drugs based on it. Future studies could focus on the direction of immunotherapy targeting Aβ, and apply these drugs to therapies targeting Tau protein.

Investigating the Potential Impact of LH on the Progression of Alzheimer’s Disease via Microglia Activation and C/EBPβ pathway

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that causes irreversible cognitive decline and memory loss. The disproportionate effect of AD on postmenopausal women prompts investigation into the role of hormonal changes in disease pathogenesis. However, previous studies on estrogen replacement therapies have shown inconsistent results. Therefore, further confirmation is needed to ensure the independent effects of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on AD pathology. Our study will 1) focus on microglial activation pathway 2) focus on the LH-C/EBPβ-AEP pathway and its potential influence on AD progression.Methods: Using cell lines to investigate whether microglial activation is present. HMC3 cells will be treated with LH or control phosphate buffered saline (PBS). Carry out Western Blot (WB) and qPCR to confirm presence of cytokines, which is the product of microglial activation. Using 3xTg-AD mice treated with LH or control PBS. To identify AD progression, immunofluorescent (IF) micrograph will be used to quantify amyloid-beta (Aβ) load. WB and qPCR will be used to identify cytokines. Morris water maze (MWM) will be carried out for cognitive testing. Using an ovariectomized mice model to investigate the LH-C/EBPβ-AEP pathway. Mice will be treated with LH antibodies or control IgG, followed by assessments using IVIS imaging and MWM test to measure spatial memory. IF, WB and qPCR will be used to quantify Aβ and Tau protein levels and gene expression changes. Furthermore, the study will explore the precise relationship between LH and C/EBPβ expression through inhibition experiments targeting AKT and ERK1/2 signaling pathways.Expected results: Our hypothesis is that LH activates microglia, with both pro-inflammatory and anti-inflammatory cytokine released. This change in microglia function suggests LH has an effect on microglia and hence removal of Aβ plaques. Another hypothesis is that LH antibody manages to cross the blood-brain barrier. The cognitive ability will be improved in LH-Ab treated mice with reduced Aβ and Tau protein levels and downregulation of the C/EBPβ–AEP/δ-secretase pathway. Simultaneously, we expect that there will be a positive correlation between LH levels and expression of C/EBPβ-related pathways, suggesting the involvement of AKT and ERK1/2 signaling pathways in AD progression.Conclusion: This study aims to provide evidence for the link between LH activation of the C/EBPβ pathway and AEP production, promoting our understanding of AD pathogenesis. The insights gained may implicate therapeutic strategies targeting LH mechanisms in postmenopausal women at risk of AD.

Heterologous expressing melittin in a probiotic yeast to evaluate its function for promoting NSC-34 regeneration

Melittin is a bioactive peptide and the predominant component in bee venom (BV), studied for its many medical properties, such as antibacterial, anti-inflammatory, anti-arthritis, nerve damage reduction, and muscle cell regeneration. Melittin is primarily obtained through natural extraction and chemical synthesis; however, both methods have limitations and cannot be used for mass production. This study established a heterologous melittin expression system in the probiotic yeast Kluyveromyces marxianus. This yeast was selected for its advantages in stress tolerance and high secreted protein yields, simplifying purification. A > 95% high-purity melittin (MET) and its precursor promelittin (ProMET) were successfully produced and purified at 1.68 μg/mL and 3.33 μg/mL concentrations and verified through HPLC and mass spectrum. The functional test of the NSC-34 cell regeneration revealed that MET achieved the best activity compared to ProMET and the natural-extracted BV groups. Growth-related gene expressions were evaluated, including microtubule-associated protein 2 (MAP2), microtubule-associated protein Tau (MAPT), growth-associated protein 43 (GAP-43), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and acetylcholine esterase (AChE). The results indicated that treating MET increased MAP2, GAP-43, and VAChT expressions, in which cholinergic signaling is related to neurological functions. A heterologously expressed melittin in a probiotic yeast and its potential for promoting NSC-34 regeneration described here facilitate commercial and therapeutic use.Key points• MET and its precursor ProMET were successfully hetero-expressed in K. marxianus• > 95% high-purity MET and ProMET were purified at 1.68 μg/mL and 3.33 μg/mL• MET has no cytotoxicity toward NSC-34 and significantly promotes NSC-34 growth

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p<0.001 for both; t-tau: p<0.001 and p=0.041; Aβ40: p<0.001 and p=0.050; Aβ42: p<0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p<0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p<0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p<0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p<0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Step Pulse-Mediated Low-Triggering Potential Electrochemiluminescence of Polyfluorene Nanoparticles for Bioassay.

When the electrochemiluminescence (ECL) reaction occurs at a triggering potential beyond ±1.0 V, the interference from the adverse oxidation-reduction reaction cannot be ignored. However, currently reported anode ECL usually occurs above +1.0 V. This study innovatively developed a convenient and simple step pulse (SP) method to modulate the low ECL triggering potential of poly [(9,9-dioctyl-fluorenyl-2,7-diacyl)-alt-co-(9-hexyl-3,6-carbazole)] (PFA) nanoparticles (NPs). Compared to cyclic voltammetry with a triggering potential exceeding +1.25 V for PFA NPs, SP scanning enabled PFA NPs to exhibit a strong and stable ECL emission with a triggering potential as low as +0.75 V and tripropylamine (TPrA) as a coreactant. PFA NPs coupled an efficient aptameric recognition-driven cascade nucleic acid amplification strategy to construct a sensitive biosensing platform for measuring phosphorylated Tau (p-Tau) protein as an Alzheimer's disease biomarker. p-Tau could release the secondary target (ST) chain through the aptameric recognition reaction with the aptamer, and the released ST could further trigger cascade catalytic hairpin assembly (CHA) and rolling circle amplification (RCA) at the PFA NP-modified electrode, producing a large number of long chains. The large amount of G-quadruplex/hemin formed by long chains and hemin will consume the ECL quencher H2O2 added in detection solution, thereby restoring the ECL signal and enabling the low potential quantitative analysis of p-Tau with a limit of detection of 4.15 fg/mL. SP technique provides a new way to reduce ECL triggering potential, and PFA NPs create a promising low-triggering potential ECL-sensing platform for bioanalysis.

Phosphorylated tau protein serum levels increase over time in patients with chronic heart failure

Abstract Background/Introduction Amongst various potential biomarkers associated with cognitive deficits, phosphorylated Tau (pTau) appears to link brain and cardiac abnormalities through a systemic tauopathy pathway. Purpose A recent report on the potential importance of myocardial pTau in chronic heart failure (HF) prompted the here described longitudinal quantification of circulating pTau serum levels in patients with HF. We hypothesized that serum pTau accumulates in HF and is associated with markers of myocardial dysfunction. Methods Eligible patients within the prospective, investigator-initiated, monocentric follow-up study Cognition.Matters-HF were older than 18 years, suffered from stable chronic HF and were free from major neurological or psychiatric disorders. Beyond the cardiological assessment including transthoracic echocardiography and six minute walking distance (6-MWD), investigations at baseline, 1 year and 3 years comprised extensive, domain-specific psychological testing and volumetric brain magnetic resonance imaging. Serum pTau was measured using the pTau181 advantage kit. Results Serum samples were available from 78 patients. Mean age was 63±10 years and 87% were men. Serum pTau longitudinally increased from a median of 1.05 (quartiles 0.26, 1.21) pg/ml at baseline to 1.84 (1.36, 3.60) pg/ml after 3 years (p<0.001). During that time period, LVEF, NT-proBNP, 6-MWD and the hippocampal volume remained unaltered, whereas global brain volume and cortical thickness shrank age-appropriately. Cognitive testing revealed that domain-specific T-scores within 36 months remained stable for attentional intensity and executive functioning, and even improved for memory. When we entered baseline values of age and above-mentioned cardiac, brain-volumetric, and cognitive parameters into a multivariable regression model predicting log-transformed pTau, only age (β=0.34), NT-proBNP (β=0.24) and GBV (β=0.26) were independently associated with pTau serum levels (R2=0.18). Consistently, at 36 months, the same predictors were selected by the model (R2=0.29): age (β=0.41), NT-proBNP (β=0.43), and global brain volume (β=0.26). Moreover, higher baseline pTau (β=0.23) and lower 6-MWD (β=-0.39) independently predicted ΔpTau with an explained variance (R2) of 0.24. Conclusions We observed a prominent increase of serum pTau over time, which was predicted by prevalent myocardial dysfunction. Moreover, absolute NT-proBNP levels were independently associated with absolute pTau serum levels, along with age and global brain volume. Mechanistically, phosphorylation of cardiac tau is thought to destabilize its interaction with microtubules causing microtubule detyronisation and increased myocardial stiffness through enhancing the mechanical resistance of contracting cardiomyocytes. The etiological role of pTau in the development of HF and the potential of serum pTau as a novel biomarker of chronic HF warrants further studies.

Photobiomodulation as a Potential Treatment for Alzheimer’s Disease: A Review Paper

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease’s underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer’s disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.

Phosphorylated tau in cerebrospinal fluid-derived extracellular vesicles in Alzheimer’s disease: a pilot study

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by brain aggregation of β-amyloid (Aβ) peptides and phosphorylated tau (P-tau) proteins. Extracellular vesicles (EVs) can be isolated and studied for potential roles in disease. While several studies have tested plasma-derived EVs in AD, few have analyzed EVs from cerebrospinal fluid (CSF), which are potentially more closely related to brain changes. This study included 20 AD patients and 20 cognitively unimpaired (CU) participants. Using a novel EV isolation method based on acoustic trapping, we isolated and purified EVs from minimal CSF volumes. EVs were lysed and analyzed by immunoassays for P-tau217 and P-tau181. Isolation was confirmed through transmission electron microscopy and the presence of EV-specific markers (CD9, CD63, CD81, ATP1A3). Nanoparticle tracking analysis revealed a high variance in EV distribution. AD patients exhibited increased P-tau181 and decreased P-tau217 in EVs, leading to a higher EV P-tau181/P-tau217 ratio compared to CU. No significant differences in EV counts or sizes were observed between AD and CU groups. This study is the first to use acoustic trapping to isolate EVs from CSF and demonstrates differential P-tau content in AD-derived EVs, warranting further research to understand the relationship between these EV changes and brain pathology.

Synergistic Effect of Aβ42 and Tau Protein in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease that can't be cured at present, which is different from what we call infectious diseases, and is usually related to senile dementia. Although there is no radical cure at present, early diagnosis and intervention can delay the progress of the disease and improve the quality of life of patients. The mechanism of Aβ42 and Tau protein in AD is of great significance for early diagnosis and treatment of diseases. In this paper, the interaction between these two proteins is deeply analyzed, and their role in the pathological development of AD is discussed, and how to use this knowledge to improve the accuracy of clinical diagnosis and develop new treatment strategies.

Sleep Disorders in Alzheimer’s Disease

Alzheimer’s disease is the leading cause of dementia worldwide. Patients typically exhibit cognitive impairment, memory loss, diminished social and occupational functioning, as well as language and motor disorders. Alzheimer’s disease is characterized by the abnormal accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. These pathological changes not only disrupt neuronal function and lead to cognitive deficits, but also interfere with sleep regulation, resulting in sleep disorders. Such disturbances can diminish nighttime sleep quality and contribute to daytime functional impairments, further exacerbating cognitive decline. Therefore, exploring the interplay between cognitive impairment, Alzheimer’s disease, and sleep disorders is crucial for enhancing the quality of life of Alzheimer’s patients. This review summarizes current literature on the interconnections among Alzheimer’s disease, cognitive impairment, and sleep disorders. Sleep disturbances are prevalent in Alzheimer’s patients and can also occur in those with amnestic mild cognitive impairment, which often precedes Alzheimer’s onset. Such sleep disorders may promote and accelerate the accumulation of amyloid-β and tau proteins [1-3]. Furthermore, Alzheimer’s patients may be more vulnerable to sleep disturbances, creating a potential vicious cycle. Further investigation into these relationships may provide valuable insights for the treatment or prevention of Alzheimer’s disease.

Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer’s disease

Alzheimer’s disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin’s responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1’s anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

Deciphering the role of lipid metabolism-related genes in Alzheimer’s disease: a machine learning approach integrating Traditional Chinese Medicine

BackgroundAlzheimer’s disease (AD) represents a progressive neurodegenerative disorder characterized by the accumulation of misfolded amyloid beta protein, leading to the formation of amyloid plaques and the aggregation of tau protein into neurofibrillary tangles within the cerebral cortex. The role of carbohydrates, particularly apolipoprotein E (ApoE), is pivotal in AD pathogenesis due to its involvement in lipid and cholesterol metabolism, and its status as a genetic predisposition factor for the disease. Despite its significance, the mechanistic contributions of Lipid Metabolism-related Genes (LMGs) to AD remain inadequately elucidated. This research endeavor seeks to bridge this gap by pinpointing biomarkers indicative of early-stage AD, with an emphasis on those linked to immune cell infiltration. To this end, advanced machine-learning algorithms and data derived from the Gene Expression Omnibus (GEO) database have been employed to facilitate the identification of these biomarkers.MethodsDifferentially expressed genes (DEGs) were identified by comparing gene expression profiles between healthy individuals and Alzheimer’s disease (AD) patients, using data from two Gene Expression Omnibus (GEO) datasets: GSE5281 and GSE138260. Functional enrichment analysis was conducted to elucidate the biological relevance of the DEGs. To ensure the reliability of the results, samples were randomly divided into training and validation sets. The analysis focused on lipid metabolism-related DEGs (LMDEGs) to explore potential biomarkers for AD. Machine learning algorithms, including Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model, were applied to identify a key gene biomarker. Additionally, immune cell infiltration and its relationship with the gene biomarker were assessed using the CIBERSORT algorithm. The Integrated Traditional Chinese Medicine (ITCM) database was also referenced to identify Chinese medicines related to lipid metabolism and their possible connection to AD. This comprehensive strategy aims to integrate modern computational methods with traditional medicine to deepen our understanding of AD and its underlying mechanisms.ResultsThe study identified 137 genes from a pool of 751 lipid metabolism-related genes (LMGs) significantly associated with autophagy and immune response mechanisms. Through the application of LASSO and SVM-RFE machine-learning techniques, four genes—choline acetyl transferase (CHAT), member RAS oncogene family (RAB4A), acyl-CoA binding domain-containing protein 6 (ACBD6), and alpha-galactosidase A (GLA)—emerged as potential biomarkers for Alzheimer’s disease (AD). These genes demonstrated strong therapeutic potential due to their involvement in critical biological pathways. Notably, nine Chinese medicine compounds were identified to target these marker genes, offering a novel treatment approach for AD. Further, ceRNA network analysis revealed complex regulatory interactions involving these genes, underscoring their importance in AD pathology. CIBERSORT analysis highlighted a potential link between changes in the immune microenvironment and CHAT expression levels in AD patients, providing new insights into the immunological dimensions of the disease.ConclusionThe discovery of these gene markers offers substantial promise for the diagnosis and understanding of Alzheimer’s disease (AD). However, further investigation is necessary to validate their clinical utility. This study illuminates the role of Lipid Metabolism-related Genes (LMGs) in AD pathogenesis, offering potential targets for therapeutic intervention. It enhances our grasp of AD’s complex mechanisms and paves the way for future research aimed at refining diagnostic and treatment strategies.

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia.

Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.