Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Interval-specific likelihood ratios and probability-based models for interpreting combined CSF biomarkers for Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD) diagnosis, a cerebrospinal fluid (CSF) biomarker panel is commonly interpreted with binary cutoff values. However, these values are not generic and do not reflect the disease continuum. We explored the use of interval-specific likelihood ratios (LRs) and probability-based models for AD using a CSF biomarker panel. METHODS: CSF biomarker (Aß1-42, tTau and pTau181) data for both a clinical discovery cohort of 241 patients (measured with INNOTEST) and a clinical validation cohort of 129 patients (measured with EUROIMMUN), both including AD and non-AD dementia/cognitive complaints were retrospectively retrieved in a single-center study. Interval-specific LRs for AD were calculated and validated for univariate and combined (Aß1-42/tTau and pTau181) biomarkers, and a continuous bivariate probability-based model for AD, plotting Aß1-42/tTau versus pTau181 was constructed and validated. RESULTS: LR for AD increased as individual CSF biomarker values deviated from normal. Interval-specific LRs of a combined biomarker model showed that once one biomarker became abnormal, LRs increased even further when another biomarker largely deviated from normal, as replicated in the validation cohort. A bivariate probability-based model predicted AD with a validated accuracy of 88% on a continuous scale. CONCLUSIONS: Interval-specific LRs in a combined biomarker model and prediction of AD using a continuous bivariate biomarker probability-based model, offer a more meaningful interpretation of CSF AD biomarkers on a (semi-)continuous scale with respect to the post-test probability of AD across different assays and cohorts.

Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.

Background: Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD. Objective: This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Methods: Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules. Results: Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AßPP, Aß, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor. Conclusion: Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.

Recent advancements in the role of phytochemicals and medicinal plants in prophylaxis and management of Alzheimer's disease.

Medicinal plants and phytochemicals are some of the major sources in the treatment of various neurodegenerative disorders including Alzheimer's disease (AD). There is no FDA-approved drug to target AD pathology directly. Full cognitive restoration and management of psychosis-like symptoms are still to be achieved. Being comparatively safer with fewer side effects, medicinal plants have been among the major areas of interest to be researched. Several mechanistic pathways are involved in AD including anticholinesterase activity, glutamate toxicity, free radicals generation, Amyloid ß (Aß) toxicity, inflammation, and mitochondrial dysfunction. Various phytochemicals such as paenol, andrographolide, isoquercitrin, flavonoids, and saponins obtained from different plant sources, various medicinal plants like Spirulina maxima, Salicornia europaea, Curcuma longa, Citrus Junos Tanaka, Cassiae semen, Centella asiatica as well as various traditional medicinal plants of China, Asia, Europe, Turkey, and Iran have been found effective against one or more of these targets. Large numbers of clinical trials are under process to evaluate the role of different phytoconstituents in AD management. Out of 143 agents under clinical trials, 119 have been categorized as disease-modifying agents. The present review extensively covers the recent advancements in the usage of phytochemicals and medicinal plants in various experimental AD models. It involves clinical trials and other research works divided into three sections, including those performed in vitro, in vivo, and in humans mainly from the last five years along with disease markers and mechanistic pathways involved. However, phytochemicals should be explored further in order to achieve neurorestoration in AD.

miRNA375-3p/rapamycin mediates the mTOR pathway by decreasing PS1, enhances microglial cell activity to regulate autophagy in Alzheimer's disease.

The clinical prevention, diagnosis, treatment, and drug development of Alzheimer's disease (AD) require urgent detection of novel targets and methods. Autophagy and microglia are significantly associated with the pathogenesis of early AD. This study indicated that microRNA-375-3p can inhibit autophagy by promoting mTOR phosphorylation in normal physiological conditions, while microRNA-375-3p promoted autophagy and enhanced neural repair by inhibiting the expression of presenilin 1 in early AD pathogenesis. Furthermore, co-treatment of rapamycin, and microRNA-375-3p can synergistically promote the autophagy and microglial activation in a neuroprotective manner, clear Aß accumulation, repair nerve damage, and alleviate cognitive dysfunction and memory defects in APP/PS1 TG mice. This research revealed the impact and mechanism of miR375-3p on the early stage of AD through in vivo and in vitro experiments and provides new ideas and directions for the early treatment of AD.

Hyperspectral retinal imaging in Alzheimer's disease and age-related macular degeneration: a review.

While Alzheimer's disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimer's disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation.

Exploring the connection between EU-funded research and methodological approaches: insights from a retrospective analysis.

BACKGROUND: Over the last two decades, substantial investments have been directed towards supporting fundamental and applied research in Alzheimer's disease (AD), breast cancer (BC), and prostate cancer (PC), which continue to pose significant health challenges. Recently, the Joint Research Centre (JRC) of the European Commission (EC) conducted a retrospective analysis to examine the major scientific advancements resulting from EU-funded research in these disease areas and their impact on society. METHODS: Building upon this analysis, our subsequent investigation delves into the methodological approaches-both animal and non-animal models and methods-employed in AD, BC, and PC research funded under past EU framework programs (FP5, FP6, FP7, and H2020), and explored the notable research outputs associated with these approaches. RESULTS: Our findings indicate a prevalent use of animal-based methodologies in AD research, particularly evident in projects funded under H2020. Notably, projects focused on drug development, testing, or repurposing heavily relied on animal models. Conversely, research aimed at clinical trial design, patient stratification, diagnosis and diagnostic tool development, lifestyle interventions, and prevention-outputs with potential societal impact-more frequently utilised non-animal methods. Advanced investigations leveraging imaging, computational tools, biomarker discovery and organ/tissue chip technologies predominantly favoured non-animal strategies. CONCLUSIONS: These insights highlight a correlation between methodological choices and the translational potential of research outcomes, suggesting the need for a reconsideration of research strategy planning in future framework programs.

Linking the neural signature of response time variability to Alzheimer's disease pathology and cognitive functioning.

Promising evidence has suggested potential links between mind-wandering and Alzheimer's disease (AD). Yet, older adults with diagnosable neurocognitive disorders show reduced meta-awareness, thus questioning the validity of probe-assessed mind-wandering in older adults. In prior work, we employed response time variability as an objective, albeit indirect, marker of mind-wandering to identify patterns of functional connectivity that predicted mind-wandering. In the current study, we evaluated the association of this connectome-based, mind-wandering model with cerebral spinal fluid (CSF) p-tau/Aß 42 ratio in 289 older adults from the Alzheimer's Disease NeuroImaging Initiative (ADNI). Moreover, we examined if this model was similarly associated with individual differences in composite measures of global cognition, episodic memory, and executive functioning. Edges from the high response time variability model were significantly associated with CSF p-tau/Aß ratio. Furthermore, connectivity strength within edges associated with high response time variability was negatively associated with global cognition and episodic memory functioning. This study provides the first empirical support for a link between an objective neuromarker of mind-wandering and AD pathophysiology. Given the observed association between mind-wandering and cognitive functioning in older adults, interventions targeted at reducing mind-wandering, particularly before the onset of AD pathogenesis, may make a significant contribution to the prevention of AD-related cognitive decline.

Response time variability is considered an objective, albeit indirect, marker of mind-wandering. In this study, we applied a previously-derived connectome-based model of response time variability to resting-state data obtained from 289 older adults in the Alzheimer's Disease NeuroImaging Initiative. The network strength of the high response time variability model was correlated with a cerebrospinal fluid (CSF)-based ratiometric measure of amyloid and tau pathology. Additionally, our results demonstrated that the network strength in the high response time variability model was also linked with global cognition and episodic memory. This study provides the first empirical support for the association between a neuromarker of response time variability­an indirect marker of mind-wandering­and AD pathophysiology.

Modified Ce/Zr-MOF Nanoparticles Loaded with Curcumin for Alzheimer's Disease via Multifunctional Modulation.

Introduction: Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy. Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aß1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level. Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-ß deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation. Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.

Gut microbiota metabolites: potential therapeutic targets for Alzheimer's disease?

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology. Methods: In this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD. Results: The gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including ß-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance. Conclusion: Despite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.

Widespread transposable element dysregulation in human aging brains with Alzheimer's disease.

INTRODUCTION: Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD. METHODS: We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons. RESULTS: We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons. DISCUSSION: We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes. HIGHLIGHTS: Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons.

Plasmonic Nanogap-Enhanced Tunable Three-Dimensional Nanoframes in Application to Clinical Diagnosis of Alzheimer's Disease.

Advancements in nanotechnology led to significant improvements in synthesizing plasmon-enhanced nanoarchitectures for biosensor applications, and high-yield productivity at low cost is vital to step further into medical commerce. Metal nanoframes via wet chemistry are gaining attention for their homogeneous structure and outstanding catalytic and optical properties. However, nanoframe morphology should be considered delicately when brought to biosensors to utilize its superior characteristics thoroughly, and the need to prove its clinical applicability still remains. Herein, we controlled the frameworks of double-walled nanoframes (DWFs) precisely via wet chemistry to construct a homogeneous plasmon-enhanced nanotransducer for localized surface plasmon resonance biosensors. By tuning the physical properties considering the finite-difference time-domain simulation results, biomolecular interactions were feasible in the electromagnetic field-enhanced nanospace. As a result, DWF10 exhibited a 10-fold lower detection limit of 2.21 fM compared to DWF14 for tau detection. Further application into blood-based clinical and Alzheimer's disease (AD) diagnostics, notable improvement in classifying mild cognitive impairment patients against healthy controls and AD patients, was demonstrated along with impressive AUC values. Thus, in response to diverse detection methods, optimizing nanoframe dimensions such as nanogap and frame thickness to maximize sensor performance is critical to realize future POCT diagnosis.

Advanced nano delivery system for stem cell therapy for Alzheimer's disease.

Alzheimer's Disease (AD) represents one of the most significant neurodegenerative challenges of our time, with its increasing prevalence and the lack of curative treatments underscoring an urgent need for innovative therapeutic strategies. Stem cells (SCs) therapy emerges as a promising frontier, offering potential mechanisms for neuroregeneration, neuroprotection, and disease modification in AD. This article provides a comprehensive overview of the current landscape and future directions of stem cell therapy in AD treatment, addressing key aspects such as stem cell migration, differentiation, paracrine effects, and mitochondrial translocation. Despite the promising therapeutic mechanisms of SCs, translating these findings into clinical applications faces substantial hurdles, including production scalability, quality control, ethical concerns, immunogenicity, and regulatory challenges. Furthermore, we delve into emerging trends in stem cell modification and application, highlighting the roles of genetic engineering, biomaterials, and advanced delivery systems. Potential solutions to overcome translational barriers are discussed, emphasizing the importance of interdisciplinary collaboration, regulatory harmonization, and adaptive clinical trial designs. The article concludes with reflections on the future of stem cell therapy in AD, balancing optimism with a pragmatic recognition of the challenges ahead. As we navigate these complexities, the ultimate goal remains to translate stem cell research into safe, effective, and accessible treatments for AD, heralding a new era in the fight against this devastating disease.

Engineered 3D human neurovascular model of Alzheimer's disease to study vascular dysfunction.

The blood-brain barrier (BBB) serves as a selective filter that prevents harmful substances from entering the healthy brain. Dysfunction of this barrier is implicated in several neurological diseases. In the context of Alzheimer's disease (AD), BBB breakdown plays a significant role in both the initiation and progression of the disease. This study introduces a three-dimensional (3D) self-assembled in vitro model of the human neurovascular unit to recapitulate some of the complex interactions between the BBB and AD pathologies. It incorporates primary human brain endothelial cells, pericytes and astrocytes, and stem cell-derived neurons and astrocytes harboring Familial AD (FAD) mutations. Over an extended co-culture period, the model demonstrates increased BBB permeability, dysregulation of key endothelial and pericyte markers, and morphological alterations mirroring AD pathologies. The model enables visualization of amyloid-beta (Aß) accumulation in both neuronal and vascular compartments. This model may serve as a versatile tool for neuroscience research and drug development to provide insights into the dynamic relationship between vascular dysfunction and AD pathogenesis.

Expressing miR-282 mitigates Aß42-induced neurodegeneration in Alzheimer's model in Drosophila.

Alzheimer's disease is a complex neurodegenerative condition characterized by the accumulation of amyloid beta plaques, leading to memory loss, cognitive decline, and impaired autonomous behavior. Despite extensive research, an effective treatment remains elusive. The buildup of amyloid beta plaques (Aß42) in the brain causes oxidative stress and disrupts normal molecular signaling, adversely affecting neuron function. Previous research has identified factors that can either exacerbate or mitigate neurodegenerative diseases. Our study aimed to uncover new factors involved in the pathogenesis of Alzheimer's disease. Using Drosophila as a model organism, we employed the Gal4/UAS system to express human Aß42 in the flies' retinal neurons which led to neurodegenerative changes in their compound eyes. To identify genetic modifiers, we conducted a screen by co-expressing microRNAs and found that miR-282 acts as a suppressor. Overexpressing miR-282 in the GMR > Aß42 background reduced Aß42-induced neurodegeneration. Further analysis using prediction tools and RNA interference experiments identified three potential downstream targets of miR-282: calpain-B, knot, and scabrous. Downregulating these genes via RNA interference in the GMR > Aß42 background mitigated neurodegeneration. Our research highlights miR-282 as a novel molecule that may influence the progression of Alzheimer's disease, offering potential avenues for future therapeutic or diagnostic developments.

Real-time analysis of the biomolecular interaction between gelsolin and Aß1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different ß-amyloid protein 1-42 (Aß1-42) species, including Aß1-42 monomer (m-Aß), Aß1-42 oligomers with both low and high levels of aggregation (LLo-Aß and HLo-Aß) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aß had the strongest affinity and specificity with GSN compared with LLo-Aß and HLo-Aß. The impact of GSN on inhibiting aggregation of Aß1-42 and solubilizing Aß1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aß and the reversal of ß-sheet structure in HLo-Aß were observed, demonstrating the beneficial effects of GSN on preventing Aß from aggregation. In addition, the structure of m-Aß/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aß in its soluble state and to inhibit the fibrilization of Aß1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aß1-42, but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.

Investigating the phytochemical profile, biological potentials, morphological, and anatomical characteristics of Cyclotrichium origanifolium (Labill.) Manden. & Scheng. (Lamiaceae) from Turkey.

Cyclotrichium origanifolium, a plant widely used in Eastern and Southern Anatolia for culinary purposes, was subject of this study, which aimed to comprehensively evaluate its potential therapeutic applications. This research stands out due to its holistic approach, combining morpho-anatomical studies, chemical, and biological analyses to explore antioxidant, antidiabetic, anticholinesterase, genotoxic, and anti-genotoxic effects of methanolic and aqueous extracts, as well as flowering aerial part essential oil. It is a perennial plant, typically ranging from 10 to 40 cm in height, with a suffrutescent and highly branched growth habit. Essential oils are produced within glandular trichomes. Oil, analyzed via GC-MS/MS, revealed 24 compounds accounting for 96.4% of oil, with isomenthone (52.4%), pulegone (23.4%), and ß-pinene (9.5%) as predominant components. These findings are significant as they provide new insights into chemical composition of oils, particularly highlighting pharmacologically active compounds. Methanol extract exhibited superior antioxidant activity, correlated with high phenol and tannin content. Essential oil showed moderate inhibition of α-amylase (49.54%) and mild inhibition of acetylcholinesterase (11.84%) and butyrylcholinesterase (16.93%), suggesting potential in managing oxidative stress and neurodegenerative diseases. Study also conducted biosafety evaluations using Ames/Salmonella and Allium tests, essential for assessing genotoxic and antigenotoxic potential of natural products. Notably, significant antimicrobial effects were identified, particularly against Pseudomonas aeruginosa and Enterococcus faecalis. Comprehensive analysis and discovery of significant bioactivities position this research as a valuable contribution to field, distinguishing it from previous studies on similar species. This study provides a foundational understanding of morpho-anatomical, pharmacological, biological properties of plant, opening avenues for future research.

Transcultural Adaptation of the "Caregiver Guilt Questionnaire" (CGQ).

OBJECTIVES: To implement a transcultural adaptation of the Caregiver Guilt Questionnaire (CGQ) for the Brazilian population. METHODS: Five stages were involved in the adaptation: two independent translations by Brazilian nationals fluent in Spanish; summary of translations produced; back-translation; evaluation by expert panel of judges (n = 5); and lastly, assessment by family caregivers (n = 30). RESULTS: semantic changes were made to render the items more relevant to Brazilian culture and replicate the five factors of guilt proposed by the original questionnaire. CONCLUSIONS: A Brazilian version of the questionnaire was produced and transculturally adapted for use in Brazil, allowing future validation and application. CLINICAL IMPLICATIONS: The CGQ allows healthcare professionals to quantify feelings of guilt. Clinicians and clinical researcher can use the scale to obtain more precise interventions.

A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies.

INTRODUCTION: As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the 306VQIVYK311 aggregation-promoting hotspot found in all Tau isoforms or the 275VQIINK280 aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo. METHODS: We developed a retro-inverso, stable D-amino peptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspots which exhibit these disease-relevant attributes. RESULTS: Unlike other aggregation inhibitors, RI-AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non-toxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes. DISCUSSION: RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation Tau therapeutic and should be explored further for its disease-modifying potential for Tauopathies. HIGHLIGHTS: Our manuscript describes the development of a novel peptide inhibitor of Tau aggregation, a retro-inverso, stable D-amino peptide called RI-AG03 that displays many clinically relevant attributes. We show its efficacy in preventing Tau aggregation in both in vitro and in vivo experimental models while being non-toxic to cells. RI-AG03 also rescues a biosensor cell line that stably expresses Tau repeat domains with the P301S mutation fused to Cer/Clo and rescues aggregation-dependent phenotypes in vivo, suppressing neurodegeneration and extending lifespan. Collectively our data describe several properties and attributes of RI-AG03 that make it a promising disease-modifying candidate to explore for reducing pathogenic Tau aggregation in Tauopathies such as Alzheimer's disease. Given the real interest in reducing Tau aggregation and the potential clinical benefit of using such agents in clinical practice, RI-AG03 should be investigated further for the treatment of Tauopathies after validation in mammalian models. Tau aggregation inhibitors are the obvious first choice as Tau-based therapies as much of Tau-mediated toxicity is aggregation dependent. Indeed, there are many research efforts focusing on this therapeutic strategy with aggregation inhibitors being designed against one of the two aggregation-promoting hotspots of the Tau protein. To our knowledge, RI-AG03 is the only peptide aggregation inhibitor that inhibits aggregation of Tau by targeting both aggregation-promoting hotspot motifs simultaneously. As such, we believe that our study will have a significant impact on drug discovery efforts in this arena.