Parkinson's Diseases Research Articles

Entropy and fractal analysis of brain-related neurophysiological signals in Alzheimer's and Parkinson's disease.

Brain-related neuronal recordings, such as local field potential, electroencephalogram and magnetoencephalogram, offer the opportunity to study the complexity of the human brain at different spatial and temporal scales. The complex properties of neuronal signals are intrinsically related to the concept of 'scale-free' behavior and irregular dynamic, which cannot be fully described through standard linear methods, but can be measured by nonlinear indexes. A remarkable application of these analysis methods on electrophysiological recordings is the deep comprehension of the pathophysiology of neurodegenerative diseases, that has been shown to be associated to changes in brain activity complexity. In particular, a decrease of global complexity has been associated to Alzheimer's disease, while a local increase of brain signals complexity characterizes Parkinson's disease. Despite the recent proliferation of studies using fractal and entropy-based analysis, the application of these techniques is still far from clinical practice, due to the lack of an agreement about their correct estimation and a conclusive and shared interpretation. Along with the aim of helping towards the realization of a multidisciplinary audience to approach nonlinear methods based on the concepts of fractality and irregularity, this survey describes the implementation and proper employment of the mostly known and applied indexes in the context of Alzheimer's and Parkinson's diseases.

Therapeutic potential of lithium chloride and valproic acid against neuronopathic types of mucopolysaccharidoses through induction of the autophagy process

Mucopolysaccharidoses (MPS) are a group of inherited disorders, caused by mutations in the genes coding for proteins involved (directly or indirectly) in glycosaminoglycan (GAG) degradation. A lack or drastically decreased residual activity of a GAG-degrading enzyme leads to the storage of these compounds, thus damaging proper functions of different cells, including neurons. The disease leads to serious psycho-motor dysfunctions and death before reaching the adulthood. Until now, induction of the autophagy process was considered as one of the therapeutic strategies for treatment of diseases caused by protein aggregation (Alzheimer's, Parkinson's, and Huntington's diseases). However, this strategy has only been recently suggested as a potential therapy for MPS. In this work, we show that the pharmacological stimulation of autophagy, by using valproic acid and lithium chloride, led to accelerated degradation of accumulated GAGs. Cytotoxicity tests indicated the safety of the use of the investigated compounds. We observed an increased number of lysosomes and enhanced degradation of heparan sulfate (one of GAGs). Induction of the autophagy process was confirmed by measuring abundance of the marker proteins, including LC3-II. Moreover, inhibition of this process resulted in abolition of the valproic acid- and LiCl-mediated reduction in GAG levels. This is the first report on the possibility of using valproic acid and lithium chloride for reducing levels of GAGs in neuronopathic forms of MPS.

Exploring the Potential of Antidiabetic Agents as Therapeutic Approaches for Alzheimer's and Parkinson's Diseases: A Comprehensive Review.

Alzheimer's and Parkinson's are two prevalent neurodegenerative disorders with significant societal and healthcare burdens. The search for effective therapeutic approaches to combat these diseases has led to growing interest in exploring the potential of antidiabetic agents. This comprehensive review aims to provide a detailed overview of the current literature on using antidiabetic agents as therapeutic interventions for Alzheimer's and Parkinson's diseases. We discuss the underlying pathological mechanisms of these neurodegenerative diseases, including protein misfolding, inflammation, oxidative stress, and mitochondrial dysfunction. We then delve into the potential mechanisms by which antidiabetic agents may exert neuroprotective effects, including regulation of glucose metabolism and insulin signaling, anti-inflammatory effects, modulation of oxidative stress, and improvement of mitochondrial function and bioenergetics. We highlight in vitro, animal, and clinical studies that support the potential benefits of antidiabetic agents in reducing disease pathology and improving clinical outcomes. However, we also acknowledge these agents' limitations, variability in treatment response, and potential side effects. Furthermore, we explore emerging therapeutic targets and novel approaches, such as glucagon-like peptide-1 receptor(GLP-1R) agonists, insulin sensitizer drugs, neuroinflammation-targeted therapies, and precision medicine approaches. The review concludes by emphasizing the need for further research, including large-scale clinical trials, to validate the efficacy and safety of antidiabetic agents in treating Alzheimer's and Parkinson's disease. The collaboration between researchers, clinicians, and pharmaceutical companies is essential in advancing the field and effectively treating patients affected by these debilitating neurodegenerative disorders.

Calpain signaling: from biology to therapeutic opportunities in neurodegenerative disorders.

Neurodegenerative disorders represent a major and growing healthcare challenge globally. Among the numerous molecular pathways implicated in their pathogenesis, calpain signaling has emerged as a crucial player in neuronal dysfunction and cell death. Calpain is a family of calcium-dependent cysteine proteases that is involved in many biological processes, such as signal transduction, cytoskeleton remodeling, and protein turnover. Dysregulation of calpain activation and activity has been associated with several neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases. Understanding the intricate structure of calpains is crucial for unraveling their roles in cellular physiology and their implications in pathology. In addition, the identification of diverse abnormalities in both humans and other animal models with deficiencies in calpain highlights the significant progress made in understanding calpain biology. In this comprehensive review, we delve into the recent roles attributed to calpains and provide an overview of the mechanisms that govern their activity during the progression of neurodegenerative diseases. The possibility of utilizing calpain inhibition as a potential therapeutic approach for treating neuronal dysfunctions in neurodegenerative disorders would be an area of interest in future calpain research.

In Situ Detection of Neuroinflammation using Multi-cellular 3D Neurovascular Unit-on-a-Chip.

The human neurovascular system is a complex network of blood vessels and brain cells that is essential to the proper functioning of the brain. In recent years, researchers have become increasingly interested in the role of this system in developing drugs to treat neuroinflammation. This process is believed to contribute to the development of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. While much remains to be learned about the precise mechanisms by which the neurovascular system interacts with the brain and how it can be targeted for therapeutic purposes, this area of research holds great promise for the future of neurology and medicine. Currently, creating neurovascular models begins with animal models, followed by testing on humans in clinical trials. However, the high number of medication failures that pass through animal testing indicates that animal models do not always reflect the outcome of human clinical trials. To overcome the challenges of neurovascular systems and the issues with animal models, we have developed a one-of-a-kind in vitro neurovascular unit-on-a-chip to accurately replicate the in vivo human neurovascular microenvironment. This neuroinflammation-on-a-chip platform has the potential to enhance the current methods of drug development and testing to treat neurodegenerative diseases. By replicating the human neurovascular unit in vitro, a more accurate representation of human physiology can be achieved compared to animal models. The ability to detect pro-inflammatory cytokines in situ and monitor physiological changes, such as barrier function, in real-time can provide an invaluable tool for evaluating the efficacy and safety of drugs. Moreover, using nano-sized graphene oxide for in situ detection of inflammatory responses is an innovative approach that can advance the field of neuroinflammation research. Overall, our developed neuroinflammation-on-a-chip system has the potential to provide a more efficient and effective method for developing drugs for treating neurodegenerative diseases and other central nervous system (CNS) diseases.

The Intersections of Artificial Intelligence, Brain Imaging Tools and Diagnostics for Neurodegenerative Diseases

This paper explores the fascinating topics of artificial intelligence (AI), brain imaging tools, and diagnostics for neurodegenerative diseases. By examining the advancements in AI algorithms and their integration with cutting-edge brain imaging technologies, this publication displays the potential of these approaches to revolutionize the diagnoses and understanding of neurodegenerative disorders. Through an analysis of recent studies, this paper highlights the significant progress made by utilizing AI-powered tools, enhancing the accuracy, efficiency, and early detection of conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. Ultimately, this research underscores the transformative role that AI and brain imaging can play in the field of neurodegenerative disease diagnostics, paving the way for improved patient care and better outcomes.
 In addition to exploring the current state of AI and brain imaging tools in neurodegenerative disease diagnostics, my paper also dives into the potential future applications and challenges in this rapidly evolving field. It discusses the ethics of AI-driven diagnostic methods, emphasizing the importance of ensuring patient privacy, informed consent, and equitable access to these technologies.

Inhibition of Enzymes Involved in Neurodegenerative Disorders and Aβ1-40 Aggregation by Citrus limon Peel Polyphenol Extract.

Alzheimer's (AD) and Parkinson's diseases (PD) are multifactorial neurogenerative disorders of the Central Nervous System causing severe cognitive and motor deficits in elderly people. Because treatment of AD and PD by synthetic drugs alleviates the symptoms often inducing side effects, many studies have aimed to find neuroprotective properties of diet polyphenols, compounds known to act on different cell signaling pathways. In this article, we analyzed the effect of polyphenols obtained from the agro-food industry waste of Citrus limon peel (LPE) on key enzymes of cholinergic and aminergic neurotransmission, such as butyryl cholinesterase (BuChE) and monoamine oxidases (MAO)-A/B, on Aβ1-40 aggregation and on superoxide dismutase (SOD) 1/2 that affect oxidative stress. In our in vitro assays, LPE acts as an enzyme inhibitor on BuChE (IC50 ~ 73 µM), MAO-A/B (IC50 ~ 80 µM), SOD 1/2 (IC50 ~ 10-20 µM) and interferes with Aβ1-40 peptide aggregation (IC50 ~ 170 µM). These results demonstrate that LPE behaves as a multitargeting agent against key factors of AD and PD by inhibiting to various extents BuChE, MAOs, and SODs and reducing Aβ-fibril aggregation. Therefore, LPE is a promising candidate for the prevention and management of AD and PD symptoms in combination with pharmacological therapies.

Improved prediction of 5-year mortality by updating the chronic related score for risk profiling in the general population: lessons from the italian region of Lombardy.

The aim of this study was to improve the performance of the Chronic Related Score (CReSc) in predicting mortality and healthcare needs in the general population. A population-based study was conducted, including all beneficiaries of the Regional Health Service of Lombardy, Italy, aged 18 years or older in January 2015. Each individual was classified as exposed or unexposed to 69 candidate predictors measured before baseline, updated to include four mental health disorders. Conditions independently associated with 5-year mortality were selected using the Cox regression model on a random sample including 5.4 million citizens. The predictive performance of the obtained CReSc-2.0 was assessed on the remaining 2.7 million citizens through discrimination and calibration. A total of 35 conditions significantly contributed to the CReSc-2.0, among which Alzheimer's and Parkinson's diseases, dementia, heart failure, active neoplasm, and kidney dialysis contributed the most to the score. Approximately 36% of citizens suffered from at least one condition. CReSc-2.0 discrimination performance was remarkable, with an area under the receiver operating characteristic curve of 0.83. Trends toward increasing short-term (1-year) and long-term (5-year) rates of mortality, hospital admission, hospital stay, and healthcare costs were observed as CReSc-2.0 increased. CReSC-2.0 represents an improved tool for stratifying populations according to healthcare needs.

The exposome in the context of preventive measures for Alzheimer's and Parkinson's diseases

Preventive measures addressing the exposome can counteract neurodegenerative diseases. This article gives an overview on the influence of general and individual exogenous factors (environmental influences and lifestyle changes) as well as endogenous factors (e.g. metabolic alterations) on the development and progression of Alzheimer's disease (AD) and Parkinson's disease (PD). Summary and evaluation of current scientific studies and evidence regarding the exposome and prevention of AD and PD. Numerous studies could demonstrate apotential influence of environmental influences associated with industrialization (general exogenous factors), such as pesticides, solvents or air pollution on the development of AD and PD. Additionally, individually addressable changes of lifestyle (individual exogenous factors, e.g. physical activity, cognitive stimulation, nutrition and sleep) contribute to disease protection and modification and are becoming increasingly more important in light of still limited therapeutic interventions. Moreover, other exogenous factors (medication, noise pollution, head trauma and heavy metals) are discussed as risk factors for AD and/or PD. Endogenous factors (e.g., changes of the enteral microbiome, systemic inflammation and neuroinflammation, metabolic changes) can contribute to disease development by a higher potential for interacting with exogenous factors. Despite the comprehensive scientific evidence confirming the significance of the exposome for the pathogenesis of AD and PD, the great potential of preventive measures has not yet been exploited. A clarification of the high potential of lifestyle changes should be atherapeutic standard not only for individuals with manifest PD/AD but also for individuals with a risk profile or with suspected prodromal disease. Further investigations on the influence of environmental factors and the implementation of preventive strategies to avoid exposure should be the focus of international efforts.

Synergistic Screening of Peptide-Based Biotechnological Drug Candidates for Neurodegenerative Diseases Using Yeast Display and Phage Display.

Peptide therapeutics are robust and promising molecules for treating diverse disease conditions. These molecules can be developed from naturally occurring or mimicking native peptides, through rational design and peptide libraries. We developed a new platform for the rapid screening of the peptide therapeutics for disease targets. In the course of the study, we aimed to employ our platform to screen a new generation of peptide therapeutic candidates against aggregation-prone protein targets. Two peptide drug candidates were screened for protein aggregation-prone diseases, namely, Parkinson's and Alzheimer's diseases. Currently, there are several therapeutic applications that are only effective in masking or slowing down symptom development. Nonetheless, different approaches are being developed for inhibiting amyloid aggregation in the secondary nucleation phase, which is critical for amyloid fibril formation. Instead of targeting secondary nucleated protein structures, we tried to inhibit the aggregation of monomeric amyloid units as a novel approach for halting the disease condition. To achieve this, we combined yeast surface display and phage display library platforms. We expressed α-synuclein, amyloid β40, and amyloid β42 on the yeast surface, and we selected peptides by using phage display library. After iterative biopanning cycles optimized for yeast cells, several peptides were selected for interaction studies. All of the peptides have been used for in vitro characterization methods, which are quartz crystal microbalance-dissipation (QCM-D) measurement, atomic force microscopy (AFM) imaging, dot-blotting, and ThT assay, and some of them have yielded promising results in blocking fibrillization. The rest of the peptides, although, interacted with amyloid units which made them usable as a sensor molecule candidate. Therefore, peptides selected by yeast surface display and phage display library combination are good choice for diverse disease-prone molecule inhibition, particularly those inhibiting fibrillization. Additionally, these selected peptides can be used as drugs and sensors to detect diseases quickly and halt disease progression.

The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils.

The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer's and Parkinson's diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting α-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15-20 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed.

Mortality in Women across the FMR1 CGG Repeat Range: The Neuroprotective Effect of Higher Education.

Higher education has been shown to have neuroprotective effects, reducing the risk of Alzheimer's and Parkinson's diseases, slowing the rate of age-related cognitive decline, and is associated with lower rates of early mortality. In the present study, the association between higher education, fragile X messenger ribonucleoprotein 1 (FMR1) cytosine-guanine-guanine (CGG) repeat number, and mortality before life expectancy was investigated in a population cohort of women born in 1939. The findings revealed a significant interaction between years of higher education and CGG repeat number. Counter to the study's hypothesis, the effects of higher education became more pronounced as the number of CGG repeats increased. There was no effect of years of higher education on early mortality for women who had 25 repeats, while each year of higher education decreased the hazard of early mortality by 8% for women who had 30 repeats. For women with 41 repeats, the hazard was decreased by 14% for each additional year of higher education. The interaction remained significant after controlling for IQ and family socioeconomic status (SES) measured during high school, as well as factors measured during adulthood (family, psychosocial, health, and financial factors). The results are interpreted in the context of differential sensitivity to the environment, a conceptualization that posits that some people are more reactive to both negative and positive environmental conditions. Expansions in CGG repeats have been shown in previous FMR1 research to manifest such a differential sensitivity pattern.

3D bioprinting: from the functional restitution of organs and tissues to the modeling of chronic degenerative diseases

In order to overcome the long wait of patients in queues to receive a donated organ and the advancement of chronic degenerative diseases, regenerative medicine introduced 3D bioprinting. This study aims to expose the possibilities arising from the use of 3D bioprinting in organ transplantation and in the modeling of chronic degenerative diseases. A bibliographic review was carried out using the PubMed and SciELO databases, published between 1993 (due to its relevance) and 2023, no language restriction. By exploring the techniques, it was observed that biomodels created in vivo and in vitro, especially from induced pluripotent stem cells (iPSCs), the main target of this study, mimicked the architecture and physiology of bone, liver, heart tissue and even neural progenitor cells, which impact on the modeling of Parkinson's and Alzheimer's diseases. Despite the existing challenges to reproducing functional organs on a clinical scale, 3D bioprinting is a promising technology that promises to revolutionize the field of regenerative medicine and resolve, in a few years, these obstacles that cause high morbidity and mortality.

Caffeic acid recarbonization: A green chemistry, sustainable carbon nano material platform to intervene in neurodegeneration induced by emerging contaminants

Environmental agents such as pesticides, weedicides and herbicides (collectively referred to as pesticides) are associated with the onset and pathogenesis of neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's (AD) diseases. The development of blood-brain barrier (BBB)-penetrating therapeutic candidates to both prevent and treat the aforementioned xenotoxicant-induced neurodegenerative disorders remains an unmet need. Here, we examine whether caffeic-acid based Carbon Quantum Dots (CACQDs) can intervene in pesticide-associated onset and progress of the PD phenotype. Pulse-chase fluorescence analyses revealed that CACQDs intervene in the soluble-to-toxic transformation of the amyloid-forming protein model Hen Egg White Lysozyme (HEWL). The sp2-rich CACQDs also scavenged free radicals, a milestone along the PD trajectory. In-vitro, CACQDs introduced into a human neuroblastoma-derived cell line (SH-SY5Y) demonstrated negligible cytotoxicity up to 5 mg/mL and protected the cell line against oxidative stress-induced neuronal injury induced by the pesticide and potent neurotoxin, paraquat. Our findings suggest that the potentially BBB-penetrating CACQDs derived from caffeic acid hold promise for mitigating neurodegenerative disorders associated with environmental pesticides and xenobiotic neurotoxicants. Importantly, CACQDs sourced from coffee, coupled with their facile synthesis, represent a sustainable, green chemistry platform for generating interventional candidates in neurodegeneration.

Are high copper levels related to Alzheimer's and Parkinson's diseases? A systematic review and meta-analysis of articles published between 2011 and 2022.

Copper performs an important role in the brain, but in high levels it can be neurotoxic. Further, some authors have described that copper dyshomeostasis could be related with neurodegenerative diseases. Thus, this review was performed to observe whether high copper levels are related to Alzheimer's and Parkinson's diseases (AD and PD), using the literature published recently. Articles that measured copper levels in AD or PD patients was included, as well as they that measured copper levels in models used to mimic these diseases. Also, results about high copper levels effects and its relationship with AD and PD observed in laboratory animals are considered. In summary, 38 and 24 articles with AD and PD patients were included, respectively. Despite of the heterogeneity between the studies in humans, meta-analysis has demonstrated that there is an increase in free and total copper levels in the blood of AD patients compared to controls, and a decrease in copper levels in PD patients. A decrease in the metal content in postmortem brain tissue was observed in AD and PD. In manuscripts using animal models that mimic AD and PD, it was included seven and three articles, respectively. Two of them have reported an increase in copper concentrations in AD model, and one in PD model. Finally, studies with laboratory animals have concluded that high copper levels are related to oxidative stress, neuroinflammation, mitochondrial dysfunction, changes in neurotransmitter levels, cell death, and reduced both cognitive and locomotor activity, which are also described in AD or PD.

Reactive astrocytes associated with prion disease impair the blood brain barrier

BackgroundImpairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In prion disease, increased BBB permeability was reported 40 years ago, yet the mechanisms behind the loss of BBB integrity have never been explored. Recently, we showed that reactive astrocytes associated with prion diseases are neurotoxic. The current work examines the potential link between astrocyte reactivity and BBB breakdown. ResultsIn prion-infected mice, the loss of BBB integrity and aberrant localization of aquaporin 4 (AQP4), a sign of retraction of astrocytic endfeet from blood vessels, were noticeable prior to disease onset. Gaps in cell-to-cell junctions along blood vessels, together with downregulation of Occludin, Claudin-5 and VE-cadherin, which constitute tight and adherens junctions, suggested that loss of BBB integrity is linked with degeneration of vascular endothelial cells. In contrast to cells isolated from non-infected adult mice, endothelial cells originating from prion-infected mice displayed disease-associated changes, including lower levels of Occludin, Claudin-5 and VE-cadherin expression, impaired tight and adherens junctions, and reduced trans-endothelial electrical resistance (TEER). Endothelial cells isolated from non-infected mice, when co-cultured with reactive astrocytes isolated from prion-infected animals or treated with media conditioned by the reactive astrocytes, developed the disease-associated phenotype observed in the endothelial cells from prion-infected mice. Reactive astrocytes were found to produce high levels of secreted IL-6, and treatment of endothelial monolayers originating from non-infected animals with recombinant IL-6 alone reduced their TEER. Remarkably, treatment with extracellular vesicles produced by normal astrocytes partially reversed the disease phenotype of endothelial cells isolated from prion-infected animals. ConclusionsTo our knowledge, the current work is the first to illustrate early BBB breakdown in prion disease and to document that reactive astrocytes associated with prion disease are detrimental to BBB integrity. Moreover, our findings suggest that the harmful effects are linked to proinflammatory factors secreted by reactive astrocytes.

Quantitative flow cytometric selection of tau conformational nanobodies specific for pathological aggregates.

Single-domain antibodies, also known as nanobodies, are broadly important for studying the structure and conformational states of several classes of proteins, including membrane proteins, enzymes, and amyloidogenic proteins. Conformational nanobodies specific for aggregated conformations of amyloidogenic proteins are particularly needed to better target and study aggregates associated with a growing class of associated diseases, especially neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, there are few reported nanobodies with both conformational and sequence specificity for amyloid aggregates, especially for large and complex proteins such as the tau protein associated with Alzheimer's disease, due to difficulties in selecting nanobodies that bind to complex aggregated proteins. Here, we report the selection of conformational nanobodies that selectively recognize aggregated (fibrillar) tau relative to soluble (monomeric) tau. Notably, we demonstrate that these nanobodies can be directly isolated from immune libraries using quantitative flow cytometric sorting of yeast-displayed libraries against tau aggregates conjugated to quantum dots, and this process eliminates the need for secondary nanobody screening. The isolated nanobodies demonstrate conformational specificity for tau aggregates in brain samples from both a transgenic mouse model and human tauopathies. We expect that our facile approach will be broadly useful for isolating conformational nanobodies against diverse amyloid aggregates and other complex antigens.

α-Synuclein Aggregation Is Triggered by Oligomeric Amyloid-β 42 via Heterogeneous Primary Nucleation.

An increasing number of cases where amyloids of different proteins are found in the same patient are being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer's and Parkinson's diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we show that soluble species containing amyloid-β can induce the aggregation of α-synuclein. Fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated but not as part of the core of the fibrils. Importantly, by global kinetic analysis, we found that the aggregation of α-synuclein under these conditions occurs via heterogeneous primary nucleation, triggered by soluble aggregates containing amyloid-β.

Meningeal T cells function in the central nervous system homeostasis and neurodegenerative diseases.

Recently, a rising interest is given to neuroimmune communication in physiological and neuropathological conditions. Meningeal immunity is a complex immune environment housing different types of immune cells. Here, we focus on meningeal T cells, possibly the most explored aspect of neuro-immune cell interactions. Emerging data have shown that meningeal T cells play a crucial role in the pathogenesis of several neurodegenerative disorders, including multiple sclerosis, Alzheimer's, Parkinson's, and Huntington's diseases. This review highlights how meningeal T cells may contribute to immune surveillance of the central nervous system (CNS) and regulate neurobehavioral functions through the secretion of cytokines. Overall, this review assesses the recent knowledge of meningeal T cells and their effects on CNS functioning in both health and disease conditions and the underlying mechanisms.

Underlying Mechanisms of Brain Aging and Neurodegenerative Diseases as Potential Targets for Preventive or Therapeutic Strategies Using Phytochemicals.

During aging, several tissues and biological systems undergo a progressive decline in function, leading to age-associated diseases such as neurodegenerative, inflammatory, metabolic, and cardiovascular diseases and cancer. In this review, we focus on the molecular underpinning of senescence and neurodegeneration related to age-associated brain diseases, in particular, Alzheimer's and Parkinson's diseases, along with introducing nutrients or phytochemicals that modulate age-associated molecular dysfunctions, potentially offering preventive or therapeutic benefits. Based on current knowledge, the dysregulation of microglia genes and neuroinflammation, telomere attrition, neuronal stem cell degradation, vascular system dysfunction, reactive oxygen species, loss of chromosome X inactivation in females, and gut microbiome dysbiosis have been seen to play pivotal roles in neurodegeneration in an interactive manner. There are several phytochemicals (e.g., curcumin, EGCG, fucoidan, galangin, astin C, apigenin, resveratrol, phytic acid, acacetin, daucosterol, silibinin, sulforaphane, withaferin A, and betulinic acid) that modulate the dysfunction of one or several key genes (e.g., TREM2, C3, C3aR1, TNFA, NF-kb, TGFB1&2, SIRT1&6, HMGB1, and STING) affected in the aged brain. Although phytochemicals have shown promise in slowing down the progression of age-related brain diseases, more studies to identify their efficacy, alone or in combinations, in preclinical systems can help to design novel nutritional strategies for the management of neurodegenerative diseases in humans.