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Neurodegenerative disorders (NDs) are conditions marked by progressively escalating inflammation that leads to the degeneration of neuronal structure and function. There is an increasing interest in natural compounds, especially those from pharmaceutical plants, with neuroprotective properties as part of potential therapeutic interventions. Thus, the rich bioactive content of the perennial herb rosemary (Rosmarinus officinalis) is thoroughly reviewed in this article, with an emphasis on its pleiotropic pharmacological properties, including its antioxidant, anti-inflammatory, and neuroprotective health-promoting effects. In addition, a comprehensive analysis of the existing scientific literature on the potential use of rosemary and its bioactive constituents in treating neurodegenerative disorders was also conducted. Rosemary and its bioactives’ chemical properties and neuroprotective mechanisms are discussed, focusing on their ability to mitigate oxidative stress, reduce inflammation, and modulate neurotransmitter activity. The role of rosemary in enhancing cognitive function, attenuating neuronal apoptosis, and promoting neurogenesis is outlined. Key bioactive components, such as rosmarinic acid and carnosic acid, are also highlighted for their neuroprotective act. The promising outcomes of the conducted pre-clinical studies or clinical trials confirm the efficacy of rosemary in preventing or alleviating Alzheimer’s and Parkinson’s diseases both in vitro (in cells) and in vivo (in animal models of NDs). From this perspective, the applications of rosemary’s bio-functional compounds and extracts in the food, cosmetics, and pharmaceutical sectors are also presented; in the latter, we discuss their use against neurodegenerative disorders, either alone or as adjuvant therapies. This paper critically evaluates these studies’ methodological approaches and outcomes, providing insights into the current state of the clinical research and identifying potential avenues for future investigation. All findings presented herein contribute to the growing body of literature and support the exploration of natural compounds as promising candidates for novel applications and neuroprotective interventions, paving the way for more applied scientific research. Full article

Alzheimer’s disease (AD) is a neurodegenerative process responsible for almost 70% of all cases of dementia. The clinical signs consist in progressive and irreversible loss of memory, cognitive, and behavioral functions. The main histopathological hallmark is the accumulation of amyloid-ß (Aß) peptide fibrils in the brain. To date, the origin of Aß has not been determined. Recent studies have shown that the gut microbiota produces Aß, and dysbiotic states have been identified in AD patients and animal models of AD. Starting from the hypothesis that maintaining or restoring the microbiota’s eubiosis is essential to control Aß’s production and deposition in the brain, we used a mixture of probiotics and prebiotics (symbiotic) to treat APPPS1 male and female mice, an animal model of AD, from 2 to 8 months of age and evaluated their cognitive performances, mucus secretion, Aβ serum concentration, and microbiota composition. The results showed that the treatment was able to prevent the memory deficits, the reduced mucus secretion, the increased Aβ blood levels, and the imbalance in the gut microbiota found in APPPS1 mice. The present study demonstrates that the gut–brain axis plays a critical role in the genesis of cognitive impairment, and that modulation of the gut microbiota can ameliorate AD’s symptomatology. Full article

A phospholipid bilayer is a typical structure that serves crucial functions in various cells and organelles. However, it is not unusual for it to take part in pathological processes. The cell membrane may be a binding target for amyloid-forming proteins, becoming a factor modulating the oligomerization process leading to amyloid deposition—a hallmark of amyloidogenic diseases—e.g., Alzheimer’s disease. The information on the mechanisms governing the oligomerization influenced by the protein–membrane interactions is scarce. Therefore, our study aims to describe the interactions between DPPA, a cell membrane mimetic, and amyloidogenic protein human cystatin C. Circular dichroism spectroscopy and differential scanning calorimetry were used to monitor (i) the secondary structure of the human cystatin C and (ii) the phase transition temperature of the DPPA, during the protein–membrane interactions. NMR techniques were used to determine the protein fragments responsible for the interactions, and molecular dynamics simulations were applied to provide a molecular structure representing the interaction. The obtained data indicate that the protein interacts with DPPA, submerging itself into the bilayer via the AS region. Additionally, the interaction increases the content of α-helix within the protein’s secondary structure and stabilizes the whole molecule against denaturation. Full article

Alzheimer’s Disease is among the major chronic neurodegenerative diseases that affects more than 50 million people worldwide. This disease irreversibly destroys memory, cognition, and the overall daily activities which occur mainly among the elderly. Few drugs are approved for Alzheimer’s Disease management despite its high prevalence. To date, the available drugs in the market cannot reverse the damage of neurons caused by the disease leading to the exacerbation of symptoms and possibly death. Medicinal plants are considered a rich source of chemical constituents and have been contributing to modern drug discovery in many therapeutic areas including cancer, infectious, cardiovascular, neurodegenerative and Central Nervous System (CNS) diseases. Moreover, essential oils that are extracted from plant organs have been reported for a wide array of biological activities, and their roles as antioxidants, antiaging, cytotoxic, anti-inflammatory, antimicrobial, and enzyme inhibitory activities. This article highlights the promising potential of plants’ essential oils in the discovery of novel therapeutic options for Alzheimer’s Disease and halting its progression. In this article, 428 compounds were reported from the essential oils isolated from 21 plants. A comparative study is carried out by employing a variety of machine learning techniques, validation, and evaluation metrics, to predict essential oils’ efficacy against Alzheimer’s Disease progression. Extensive experiments on essential oil data suggest that a prediction accuracy of up to 82% can be achieved given the proper data preprocessing, feature selection, and model configuration steps. This study underscores the potential of integrating machine learning with natural product research to prioritize and expedite the identification of bioactive essential oils that could lead to effective therapeutic interventions for Alzheimer’s Disease. Further exploration and optimization of machine learning techniques could provide a robust platform for drug discovery and development, facilitating faster and more efficient screening of potential treatments. Full article

Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the “redoxome” encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as “cysteinet” in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark. Full article

The eEF2K, a member of the α-kinase family, plays a crucial role in cellular differentiation and the stability of the nervous system. The development of eEF2K inhibitors has proven to be significantly important in the treatment of diseases such as cancer and Alzheimer’s. With the advancement of big data in pharmaceuticals and the evolution of molecular generation technologies, leveraging artificial intelligence to expedite research on eEF2K inhibitors shows great potential. Based on the recently published structure of eEF2K and known inhibitor molecular structures, a generative model was used to create 1094 candidate inhibitor molecules. Analysis indicates that the model-generated molecules can comprehend the principles of molecular docking. Moreover, some of these molecules can modify the original molecular frameworks. A molecular screening strategy was devised, leading to the identification of five promising eEF2K inhibitor lead compounds. These five compound molecules demonstrated excellent thermodynamic performance when docked with eEF2K, with Vina scores of −12.12, −16.67, −15.07, −15.99, and −10.55 kcal/mol, respectively, showing a 24.27% improvement over known active inhibitor molecules. Additionally, they exhibited favorable drug-likeness. This study used deep generative models to develop eEF2K inhibitors, enabling the treatment of cancer and neurological disorders. Full article

Alzheimer’s disease is the most common cause of dementia globally. The pathogenesis is multifactorial and includes deposition of amyloid-β in the central nervous system, presence of intraneuronal neurofibrillary tangles and a decreased amount of synapses. It remains uncertain what causes the progression of the disease. Nowadays, it is suggested that the brain is connected to the gastrointestinal tract, especially the enteric nervous system and gut microbiome. Studies have found a positive association between AD and gastrointestinal diseases such as periodontitis, Helicobacter pylori infection, inflammatory bowel disease and microbiome disorders. H. pylori and its metabolites can enter the CNS via the oropharyngeal olfactory pathway and may predispose to the onset and progression of AD. Periodontitis may cause systemic inflammation of low severity with high levels of pro-inflammatory cytokines and neutrophils. Moreover, lipopolysaccharide from oral bacteria accompanies beta-amyloid in plaques that form in the brain. Increased intestinal permeability in IBS leads to neuronal inflammation from transference. Chronic inflammation may lead to beta-amyloid plaque formation in the intestinal tract that spreads to the brain via the vagus nerve. The microbiome plays an important role in many bodily functions, such as nutrient absorption and vitamin production, but it is also an important factor in the development of many diseases, including Alzheimer’s disease. Both the quantity and diversity of the microbiome change significantly in patients with AD and even in people in the preclinical stage of the disease, when symptoms are not yet present. The microbiome influences the functioning of the central nervous system through, among other things, the microbiota–gut–brain axis. Given the involvement of the microbiome in the pathogenesis of AD, antibiotic therapy, probiotics and prebiotics, and faecal transplantation are being considered as possible therapeutic options. Full article

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS−induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases. Full article

Neurodegenerative disorders (NDDs) such as Alzheimer’s (AD) and Parkinson’s (PD) are on the rise, robbing people of their memories and independence. While risk factors such as age and genetics play an important role, exciting studies suggest that a diet rich in foods from plant origin may offer a line of defense. These kinds of foods, namely fruits and vegetables, are packed with a plethora of powerful bioactive secondary metabolites (SBMs), including terpenoids, polyphenols, glucosinolates, phytosterols and capsaicinoids, which exhibit a wide range of biological activities including antioxidant, antidiabetic, antihypertensive, anti-Alzheimer’s, antiproliferative, and antimicrobial properties, associated with preventive effects in the development of chronic diseases mediated by oxidative stress such as type 2 diabetes mellitus, respiratory diseases, cancer, cardiovascular diseases, and NDDs. This review explores the potential of SBMs as theravention agents (metabolites with therapeutic and preventive action) against NDDs. By understanding the science behind plant-based prevention, we may be able to develop new strategies to promote brain health and prevent the rise in NDDs. The proposed review stands out by emphasizing the integration of multiple SBMs in plant-based foods and their potential in preventing NDDs. Previous research has often focused on individual compounds or specific foods, but this review aims to present a comprehensive fingerprint of how a diet rich in various SBMs can synergistically contribute to brain health. The risk factors related to NDD development and the diagnostic process, in addition to some examples of food-related products and medicinal plants that significantly reduce the inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), are highlighted. Full article

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. Full article

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced “track”). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkB^BDNF, TrkC^NT−3, TrkA^NGF, and TrkA^pro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkA^NGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkA^NGF, TrkA^pro-NGF, TrkB^BDNF, and TrkC^NT−3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients. Full article

Glucose and lipid metabolism are essential energy sources for the body. Dysregulation in these metabolic pathways is a significant risk factor for numerous acute and chronic diseases, including type 2 diabetes (T2DM), Alzheimer’s disease (AD), obesity, and cancer. Post-translational modifications (PTMs), which regulate protein structure, localization, function, and activity, play a crucial role in managing cellular glucose and lipid metabolism. Among these PTMs, lysine methylation stands out as a key dynamic modification vital for the epigenetic regulation of gene transcription. Emerging evidence indicates that lysine methylation significantly impacts glucose and lipid metabolism by modifying key enzymes and proteins. This review summarizes the current understanding of lysine methylation’s role and regulatory mechanisms in glucose and lipid metabolism. We highlight the involvement of methyltransferases (KMTs) and demethylases (KDMs) in generating abnormal methylation signals affecting these metabolic pathways. Additionally, we discuss the chemical biology and pharmacology of KMT and KDM inhibitors and targeted protein degraders, emphasizing their clinical implications for diseases such as diabetes, obesity, neurodegenerative disorders, and cancers. This review suggests that targeting lysine methylation in glucose and lipid metabolism could be an ideal therapeutic strategy for treating these diseases. Full article

Amidst population aging and lifestyle shifts, the incidence of neurological disorders such as stroke and Alzheimer’s disease is increasing, profoundly affecting patients’ cognitive functions and everyday life. Conventional cognitive rehabilitation approaches often necessitate substantial time and manpower, yet their outcomes remain uncertain. Although computer-assisted cognitive rehabilitation offers convenience, it can be somewhat monotonous in its experience. Virtual reality (VR) technology has introduced a novel pathway for cognitive rehabilitation, enhancing personalization and outcome assessment through tailored immersive environments and real-time data recording. This paper aims to survey the application of VR in cognitive rehabilitation, examining its impact on improving memory, attention, motor function, and social skills. A systematic review methodology was employed, following PRISMA guidelines, to identify and analyze relevant studies from 2010 to 2023. Recognizing that patients with different conditions have varying needs for the immersive and social aspects of VR, we propose the Multi-Dimensional VR Cognitive Rehabilitation Theory Model (MD-VRCRTM). This model categorizes cognitive rehabilitation technologies into six primary types: individual immersive, individual semi-immersive, individual non-immersive, multiplayer immersive, multiplayer semi-immersive, and multiplayer non-immersive rehabilitation systems. This categorization aims to cater to the specific requirements of various patients. For instance, individuals with autism spectrum disorder (ASD) may benefit more from multiplayer VR applications to enhance social skills; those with Parkinson’s disease (PD) might profit from immersive VR to facilitate motor function recovery; stroke and traumatic brain injury (TBI) patients may require highly immersive VR experiences to boost concentration and treatment efficacy; and Alzheimer’s disease (AD) patients may be better suited to non-immersive or semi-immersive VR to minimize cognitive load and receive cognitive stimulation. Full article

Alzheimer’s disease (AD) represents the most common form of dementia and affects million people worldwide, with a high social burden and considerable economic costs. AD diagnosis benefits from a well-established panel of laboratory tests that allow ruling-in patients, along with FDG and amyloid PET imaging tools. The main laboratory tests used to identify AD patients are Aβ40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated Tau 181 (pTau181) and total Tau (tTau). Although they are measured preferentially in the cerebrospinal fluid (CSF), some evidence about the possibility for blood-based determination to enter clinical practice is growing up. Unfortunately, CSF biomarkers for AD and, even more, the blood-based ones, present a few flaws, and twenty years of research in this field did not overcome these pitfalls. The tale even worsens when the issue of treating AD is addressed due to the lack of effective strategies despite the many decades of attempts by pharmaceutic industries and scientists. Amyloid-based drugs failed to stop the disease, and no neuroinflammation-based drugs have been demonstrated to work so far. Hence, only symptomatic therapy is available, with no disease-modifying treatment on hand. Such a desolate situation fully justifies the active search for novel biomarkers to be used as reliable tests for AD diagnosis and molecular targets for treating patients. Recently, a novel group of molecules has been identified to be used for AD diagnosis and follow-up, the nuclei acid-based biomarkers. Nucleic acid-based biomarkers are a composite group of extracellular molecules consisting of DNA and RNA alone or in combination with other molecules, including proteins. This review article reports the main findings from the studies carried out on these biomarkers during AD, and highlights their advantages and limitations. Full article

The diagnostic value of imaging Aβ plaques in Alzheimer’s disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [¹⁸F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [¹⁸F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [¹⁸F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [¹⁸F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [¹⁸F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [¹⁸F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [¹⁸F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [¹⁸F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [¹⁸F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [¹⁸F]flotaza to human PET studies may be worthwhile. Full article