Neurogenerative Diseases Research Articles

Virus-like Particles-Based Vaccine to Combat Neurodegenerative Diseases.

Neurodegenerative diseases are regarded as gradual, incurable conditions with an insidious onset. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most prevalent neurodegenerative diseases reported globally. Developing effective treatment strategies for neurodegenerative diseases has remained a primary objective and a huge challenge for researchers. The therapeutic medications that are now approved for the treatment of neurodegenerative diseases merely treat the symptoms; the underlying pathology is not addressed. Therefore, the emergence of novel disease-modifying therapeutic modalities such as immunotherapy has opened a new path in developing effective treatments for neurogenerative diseases. Compared to other types of subunit active vaccines, virus-like particles (VLPs) are considerably more immunogenic as they present dense and repetitive viral antigen epitopes on their surface, which can trigger both humoral and cell-mediated immune responses. They are also a much safer option than the traditional inactivated and live-attenuated vaccines since they are devoid of viral genomes and are, therefore, non-pathogenic and non-infectious. Researchers have turned their attention to VLPs as an active immunotherapy candidate for AD due to the lessons learned from the AN1792 trial. Studies have shown that they effectively induce anti-Aβ, anti-tau, and anti-α-Synuclein antibodies while avoiding T-cell-related immune reactions in animal models of AD and PD. This review compiles the findings of preclinical animal model studies and clinical investigations on VLP-based vaccines for neurogenerative diseases thus far. The technical limitations and potential difficulties associated with the future application of VLP-based vaccines in patients with neurodegenerative diseases have also been covered.

Variability in Vowel Space in Parkinson's Disease: Associations With Cognitive and Motor Impairment.

People with Parkinson's disease (PwP) typically experience impairments in vowel articulation; however, less is known about how this measure varies with speech task type and clinical characteristics such as cognitive impairment. We characterized vowel space in PwP with and without mild cognitive impairment (MCI) comparing performance across phonation, reading, and picture description tasks. We evaluated associations between vowel space and cognitive impairment, as well as motor symptom severity to elucidate the factors contributing to variability in this acoustic measure. PwP (n = 48) and age-matched controls (n = 15) performed sustained phonation of corner vowels, a reading passage, and a picture description task (Cookie Theft picture). PwP participants were classified as with normal cognition (PD-NC) or MCI (PD-MCI), and motor symptoms were assessed using the Movement Disorders Society Unified Parkingson's Disease Rating Scale Part III (MDS-UPDRS Part III). Vowel articulation index (VAI) for each task and mean difference in VAI between tasks was compared between the groups using linear mixed models adjusted for age, sex, and education. The impact of motor severity was assessed by additionally adjusting the model for MDS-UPDRS Part III score. In the adjusted mixed model, mean VAI was significantly lower in the PD-MCI group compared to the PD-NC group for all tasks. Within participants, adjusted mean differences demonstrated that all groups declined in VAI when sustained phonation was compared to either reading or picture description tasks. Adjustment for MDS-UPDRS Part III did not alter the results, suggesting no major association of motor impairment with vowel space variability within or between individuals or groups. Variability in vowel space is impacted by cognitive impairment and speech task in PwP. These findings are relevant to the further development of speech markers in PwP and other neurogenerative diseases that impact both cognitive and motor functions.

The identification of high-performing antibodies for FUS (Uniprot ID: P35637) for use in western blot, immunoprecipitation, immunofluorescence and flow cytometry

RNA-binding protein Fused-in Sarcoma (FUS) plays an essential role in various cellular processes. Mutations in the C-terminal domain region, where the nuclear localization signal (NLS) is located, causes the redistribution of FUS from the nucleus to the cytoplasm. In neurons, neurotoxic aggregates are formed as a result, contributing to neurogenerative diseases. Well-characterized anti-FUS antibodies would enable the reproducibility of FUS research, thereby benefiting the scientific community. In this study, we characterized ten FUS commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

Molecular Mechanics Demonstrate S-COMT as promising therapeutic receptor when analyzed with secondary plant metabolites

Major depressive disorder (MDD) and other psychiatric conditions are debilitating illnesses affecting millions globally. Catechol-O-methyltransferase (COMT), an enzyme that regulates dopamine and norepinephrine breakdown in the brain, has emerged as a potential therapeutic target for these disorders. This study explores the inhibitory potential of plant secondary metabolites against S-COMT using computational techniques. COMT exists in two isoforms: membrane-bound COMT (MB-COMT), primarily found in brain neurons, and soluble COMT (S-COMT), present in peripheral tissues. S-COMT, particularly in the prefrontal cortex, is crucial for regulating neurotransmitters and maintaining cognitive function. Studies suggest S-COMT variants might be linked to the development of depression, schizophrenia, and other psychiatric disorders. Current COMT inhibitors often suffer from limitations, necessitating the exploration of novel therapeutic strategies. This study employed in-silico methods to investigate plant secondary metabolites as potential S-COMT inhibitors. Here, we describe the S-COMT protein structure retrieval and validation, followed by molecular docking simulations to identify plant compounds with the strongest binding affinity to the receptor's active site. Key amino acid residues involved in these interactions were also analyzed. Furthermore, molecular dynamics simulations were conducted to assess the stability of the top-scoring protein-ligand complexes over a 100-ns timeframe. The results explored the stability of ligand binding within the active site and its impact on the overall conformation of the S-COMT receptor. Our findings highlight promising therapeutic potential for these plant-derived compounds. Further in vitro and in vivo studies are warranted to validate their efficacy and safety for potential clinical applications in treating S-COMT-related disorders. SubjectsBioinformatics and Computational Biology, Proteomics, Neurogenerative Diseases.

Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.

Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.

Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression. The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression. The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs. The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT.

A - 84 Associations between Social Vulnerability, Adaptive Functioning, and Personal Distress in Non-Demented Older Adults

Abstract Objective Though social vulnerability is associated with cognitive decline in older adults, its correlation with socioemotional and functional changes, both common in neurogenerative diseases, is often overlooked. We sought to elucidate the interplay between these critical domains in older adults with varying degrees of cognitive compromise, including participants who presented with mild cognitive impairment (MCI), subjective cognitive decline (SCD), or were cognitively unimpaired (CU), with implications for enhancing risk detection in vulnerable populations. Method Participants (N = 97; Mage = 74.64 ± 7.42 years; Meducation = 15.76 ± 2.42 years; 74.2% female) were community-dwelling older adults, along with their informants, who underwent comprehensive neuropsychological testing and responded to the Social Vulnerability Scale (SVS15), an informant-reported assessment designed to identify potential victims of exploitation. A Kruskal-Wallis test determined group differences on SVS15 (CU, SCD, MCI). Spearman correlations tested relationships among SVS15 and adaptive functioning (Assessment of Functional Capacity Interview, Financial Capacity Instrument) and personal distress, a measure of the tendency to experience anxiety/distress in response to others’ suffering (Interpersonal Reactivity Index–Personal Distress). Results SVS15 scores significantly differed across diagnostic groups, H(2) = 7.060, p < 0.05, with the MCI group performing significantly worse than the CU group, H(2) = 17.703, p < 0.05. SVS15 was significantly associated with worse functional (r = 0.571, p < 0.001) and financial (r = −0.224, p = 0.027) capacity and heightened personal distress (r = 0.390, p < 0.001). Conclusions Increased social vulnerability is associated with functional impairment and personal distress in older adults with and without cognitive impairment. Older adults with elevated emotional reactivity in distressing situations and lower levels of functional and financial capacity may be more susceptible to exploitation.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-β Toxicity in C.elegans via Distinct Mechanisms.

Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. We sought to identify probiotics that can delay Aβ-induced paralysis. Using C. elegans expressing human amyloid-β (Aβ)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.

Screening NLRP3 drug candidates in clinical development: lessons from existing and emerging technologies.

Decades of evidence positioned IL-1β as a master regulatory cytokine in acute and chronic inflammatory diseases. Approved biologics aimed at inhibiting IL-1 signaling have shown efficacy but variable safety. More recently, targeting NLRP3 activation, an upstream mediator of IL-1β, has garnered the most attention. Aberrant NLRP3 activation has been demonstrated to participate in the progression of several pathological conditions from neurogenerative diseases to cardio-metabolic syndromes and cancer. Pharmacological and genetic strategies aimed to limit NLRP3 function have proven effective in many preclinical models of diseases. These evidences have lead to a significant effort in the generation and clinical testing of small orally active molecules that can target NLRP3. In this report, we discuss different properties of these molecules with translational potential and describe the technologies currently available to screen NLRP3 targeting molecules highlighting advantages and limitations of each method.

Female sex hormones exacerbate retinal neurodegeneration.

Neurodegenerative disorders such as Alzheimer's disease and macular degeneration represent major sources of human suffering, yet the factors influencing disease severity remain poorly understood. Sex has been implicated as one potential modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration. Further, we show that this susceptibility is caused by the presence of female-specific circulating sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect. These findings provide novel insights into the pathogenesis of neurogenerative diseases and how sex hormones can impact the severity of disease. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurogenerative disorders.

Solid-state NMR backbone chemical shift assignments of α-synuclein amyloid fibrils at fast MAS regime.

The α-synuclein (α-syn) amyloid fibrils are involved in various neurogenerative diseases. Solid-state NMR (ssNMR) has been showed as a powerful tool to study α-syn aggregates. Here, we report the 1H, 13C and 15N back-bone chemical shifts of a new α-syn polymorph obtained using proton-detected ssNMR spectroscopy under fast (95kHz) magic-angle spinning conditions. The manual chemical shift assignments were cross-validated using FLYA algorithm. The secondary structural elements of α-syn fibrils were calculated using 13C chemical shift differences and TALOS software.

Exploring Varied (Green) Extraction Methods to Optimize Galia Melon Peel Antioxidant Potential

Cucumis melo L. (C. melo), commonly known as the melon, is a widely cultivated tropical fruit associated with nutritional benefits and bioactive properties. With global production reaching 40 million tons annually, the fruit processing industry generates significant waste, primarily peels, totaling 8 to 20 million tons yearly. These organic by-products are rich in bioactive compounds such as antioxidants, offering health benefits such as a reduced risk of cancer and cardiovascular diseases, as well as of diabetes and neurogenerative diseases, offering an opportunity for sustainable utilization. C. melo by-products have demonstrated various health benefits, including anti-inflammatory, analgesic, and antioxidant properties, attributed mainly to polyphenols. Recognizing the potential of melon waste, this study systematically explored different extraction methods, including stirring (ST), ultrasound (US), and pulsed electric field (PEF) methods, while considering factors such as extraction time, temperature, and solvent composition. The primary goal was to identify the most effective extraction procedures and optimal conditions for maximizing the yield of total polyphenols and antioxidant capacity (using the FRAP and DPPH methods) from C. melo peel by-products. According to the results, the optimum conditions include ST as the extraction method, an ethanolic solvent with a strength of 50%, a 150 min extraction duration, and an 80 °C extraction temperature. The maximum values of total polyphenols that can be observed are 3.75 mg gallic acid equivalents (GAE)/g of dry weight (dw) and 25.77 μmol ascorbic acid equivalents (AAE)/g dw and 34.44 μmol AAE/g dw from FRAP and DPPH antioxidant assays, respectively. The polyphenols identified were the following: gallic acid, neochlorogenic acid, catechin, chlorogenic acid, epicatechin, and kaempferol. By securing the maximum isolation of bioactive content and antioxidant activity, the research will contribute to sustainable waste management by reducing waste and developing value-added products.

Association of alcohol use with olfactory function among older adults

Background/purposeOlfactory dysfunction (OD) has been recognized as an early biomarker for neurodegenerative diseases. Identifying behaviors that increase the risk of OD is crucial for early recognition of neurogenerative diseases. Alcohol consumption can potentially impact olfaction through its neurotoxic effects. This study aims to examine the relationship between alcohol consumption and OD, using data from the National Social Life, Health, and Aging Project (NSHAP). MethodsThis cross-sectional study was conducted on data for 2757 adults from Round 1 of NSHAP. OD was defined as correctly identifying 0–3 odors in the 5-item Sniffin' Sticks test while normal olfactory function was defined as correctly identifying 4–5 odors. Multivariable logistic regression was utilized to examine the association between alcohol consumption and OD, controlling for age, race, and comorbidities. Analyses were weighted to account for the sampling design. ResultsOD was present in 23.1 % of adults. The average age among those with OD was 71.2 ± 7.8 years, compared to 66.9 ± 7.2 years in those with normal olfaction. In terms of alcohol consumption, 31.1 % of adults with OD were light-to-moderate drinkers and 7.7 % were heavy drinkers, compared to 35.6 % light-to-moderate and 7.7 % heavy drinkers in the normal olfaction group. After adjusting for age, gender, race, and education, neither light-to-moderate drinking (aOR: 0.99; 95 % CI: 0.76–1.29) nor heavy drinking (aOR: 1.24; 95 % CI: 0.83–1.85) were significantly associated with OD. ConclusionAlcohol consumption was not associated with OD after controlling for covariates. While this study provides insight into the relationship between alcohol consumption and OD, further research is needed due to conflicting results in previous studies.

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn

Backgroundβ-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear.MethodsWe generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7.ResultsDeletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density.ConclusionsThese results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

High-Dimensional Methods of Single-Cell Microglial Profiling to Enhance Understanding of Neuropathological Disease.

Microglia are the innate myeloid cells of the central nervous system (CNS) parenchyma, functionally implicated in almost every defined neuroinflammatory and neurodegenerative disorder. Current understanding of disease pathogenesis for many neuropathologies is limited and/or lacks reliable diagnostic markers, vaccines, and treatments. With the increasing aging of society and rise in neurogenerative diseases, improving our understanding of their pathogenesis is essential. Analysis of microglia from murine disease models provides an investigative tool to unravel disease processes. In many neuropathologies, bone-marrow-derived monocytes are recruited to the CNS, adopting a phenotype similar to that of microglia. This significantly confounds the accurate identification of cell-type-specific functions and downstream therapeutic targeting. The increased capacity to analyze more phenotypic markers using spectral-cytometry-based technologies allows improved separation of microglia from monocyte-derived cells. Full-spectrum profiling enables enhanced marker resolution, time-efficient analysis of >40 fluorescence parameters, and extraction of cellular autofluorescence parameters. Coupling this system with additional cytometric technologies, including cell sorting and high-parameter imaging, can improve the understanding of microglial phenotypes in disease. To this end, we provide detailed, step-by-step protocols for the analysis of murine brain tissue by high-parameter ex vivo cytometric analysis using the Aurora spectral cytometer (Cytek), including best practices for unmixing and autofluorescence extraction, cell sorting for single-cell RNA analysis, and imaging mass cytometry. Together, this provides a toolkit for researchers to comprehensively investigate microglial disease processes at protein, RNA, and spatial levels for the identification of therapeutic targets in neuropathology. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Processing the mouse brain into a single-cell suspension for microglia isolation Basic Protocol 2: Staining single-cell mouse brain suspensions for microglial phenotyping by spectral cytometry Basic Protocol 3: Flow cytometric sorting of mouse microglia for ex vivo analysis Basic Protocol 4: Processing the mouse brain for imaging mass cytometry for spatial microglia analysis.

Cell Staining Microgels Derived from a Natural Phenolic Dye: Hematoxylin Has Intriguing Biomedical Potential.

Hematoxylin (HT) as a natural phenolic dye compound is generally used together with eosin (E) dye as H&E in the histological staining of tissues. Here, we report for the first time the polymeric particle preparation from HT as poly(Hematoxylin) ((p(HT)) microgels via microemulsion method in a one-step using a benign crosslinker, glycerol diglycidyl ether (GDE). P(HT) microgels are about 10 µm and spherical in shape with a zeta potential value of -34.6 ± 2.8 mV and an isoelectric point (IEP) of pH 1.79. Interestingly, fluorescence properties of HT molecules were retained upon microgel formation, e.g., the fluorescence emission intensity of p(HT) at 343 nm was about 2.8 times less than that of the HT molecule at λex: 300 nm. P(HT) microgels are hydrolytically degradable and can be controlled by using an amount of crosslinker, GDE, e.g., about 40%, 20%, and 10% of p(HT) microgels was degraded in 15 days in aqueous environments for the microgels prepared at 100, 200, and 300% mole ratios of GDE to HT, respectively. Interestingly, HT molecules at 1000 mg/mL showed 22.7 + 0.4% cell viability whereas the p(HT) microgels exhibited a cell viability of 94.3 + 7.2% against fibroblast cells. Furthermore, even at 2000 mg/mL concentrations of HT and p(HT), the inhibition% of α-glucosidase enzyme were measured as 93.2 ± 0.3 and 81.3 ± 6.3%, respectively at a 0.03 unit/mL enzyme concentration, establishing some potential application of p(HT) microgels for neurogenerative diseases. Moreover, p(HT) microgels showed two times higher MBC values than HT molecules, e.g., 5.0 versus 2.5 mg/mL MIC values against Gram-negative E. coli and Gram-positive S. aureus, respectively.

The Prospects of Stem Cell Therapy in Neurogenerative Diseases

The Prospects of Stem Cell Therapy in Neurogenerative Diseases

Investigations Towards Tryptophan Uptake and Transport Across an In Vitro Model of the Oral Mucosa Epithelium.

Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.

Missing Puzzle Pieces in Dementia Research: HCN Channels and Theta Oscillations.

Increasing evidence indicates a role of hyperpolarization activated cation (HCN) channels in controlling the resting membrane potential, pacemaker activity, memory formation, sleep, and arousal. Their disfunction may be associated with the development of epilepsy and age-related memory decline. Neuronal hyperexcitability involved in epileptogenesis and EEG desynchronization occur in the course of dementia in human Alzheimer's Disease (AD) and animal models, nevertheless the underlying ionic and cellular mechanisms of these effects are not well understood. Some suggest that theta rhythms involved in memory formation could be used as a marker of memory disturbances in the course of neurogenerative diseases, including AD. This review focusses on the interplay between hyperpolarization HCN channels, theta oscillations, memory formation and their role(s) in dementias, including AD. While individually, each of these factors have been linked to each other with strong supportive evidence, we hope here to expand this linkage to a more inclusive picture. Thus, HCN channels could provide a molecular target for developing new therapeutic agents for preventing and/or treating dementia.

Selected phytochemicals as potent acetylcholinesterase inhibitors: An in silico prediction

In recent times, there has been a notable increase in the prevalence of Alzheimer?s disease. The disease could be managed through the inhibition of acetylcholinesterase, an enzyme associated with the degradation of acetylcholine. Plants have been used to treat neurogenerative diseases and their phytochemicals could act as acetylcholinesterase inhibitors, impeding the protein?s catalytic activity. This study includes a computational assessment of phytocompounds as potent inhibitors of the enzyme. The molecular docking calculations revealed binding affinities of -50.651 kJ/mol, -49.446 kJ/mol, - 48.400 kJ/mol, -47.977 kJ/mol, -47.839 kJ/mol, and -47.417 kJ/mol for allanxanthone B, stigmasterol, 5'-O-methyl dioncophylline D, ismailin, wistin and dioncophylline C2, respectively indicating firm binding of these molecules with the receptor. Donepezil (a native and FDA-approved drug) exhibited a binding affinity of -46.789 kJ/mol, which was significantly lower than that of the proposed phytochemicals. The hit candidates demonstrated good stability of the complex with the protein, showing smooth RMSD of ligands below 6 ? from the 200 ns molecular dynamics simulation. The thermodynamic stability from the MMPBSA method indicated the sustained spontaneity and feasibility of the adducts. Thus, the proposed hit candidates could be used as remedies for Alzheimer?s disease after experimental verification for their safety and efficacy.