The Role of Epigenetics in Neuroinflammatory-Driven Diseases

Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.     

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer’s Disease,Parkinson’s Disease and Multiple Sclerosis

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.     

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

Reticulons (RTNs) are crucial regulatory factors in the central nervous system (CNS) as well as immune system and play pleiotropic functions. In CNS, RTNs are transmembrane proteins mediating neuroanatomical plasticity and functional recovery after central nervous system injury or diseases. Moreover, RTNs, particularly RTN4 and RTN3, are involved in neurodegeneration and neuroinflammation processes. The crucial role of RTNs in the development of several neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological conditions such as brain injury or spinal cord injury, has attracted scientific interest. Reticulons, particularly RTN-4A (Nogo-A), could provide both an understanding of early pathogenesis of neurodegenerative disorders and be potential therapeutic targets which may offer effective treatment or inhibit disease progression. This review focuses on the molecular mechanisms and functions of RTNs and their potential usefulness in clinical practice as a diagnostic tool or therapeutic strategy.     

Epigenetic Regulation of Neuroinflammation in Parkinson’s Disease

Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson’s disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.     

Diosgenin Prevents Microglial Activation and Protects Dopaminergic Neurons from Lipopolysaccharide-Induced Neural Damage In Vitro and In Vivo

Background: The prevention of age-related neurodegenerative disorders is an important issue in an aging society. Microglia-mediated neuroinflammation resulting in dopaminergic neuron loss may lead to the pathogenesis of Parkinson’s disease (PD). Lipopolysaccharide (LPS), an endotoxin, induces neuroinflammatory microglial activation, contributing to dopaminergic neuron damage. Diosgenin is a phytosteroid sapogenin with a wide spectrum of pharmacological activities, e.g., anti-inflammatory activity. However, the preventive effect of diosgenin on neuroinflammation is not clear. Thus, in this study, we further investigated the neuroprotective effect of diosgenin on LPS-induced neural damage in vitro and in vivo. Methods: For in vitro experiments, primary mesencephalic neuron-glia cultures and primary microglia cultures isolated from Sprague–Dawley rats were used. Cells were pretreated with diosgenin and then stimulated with LPS. The expression of proinflammatory cytokines or tyrosine hydroxylase (TH) in the cells was analyzed. In vivo, rats were fed a diet containing 0.1% (w/w) diosgenin for 4 weeks before being administered a unilateral substantia nigra (SN) injection of LPS. Four weeks after the LPS injection, the rats were assessed for lesion severity using the amphetamine-induced rotation test and TH immunohistochemistry. Results: Diosgenin pretreatment prevented LPS-induced neurite shortening in TH-positive neurons in mesencephalic neuron-glia cultures. In addition, pretreatment of primary microglia with diosgenin significantly reduced tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Moreover, diosgenin pretreatment significantly suppressed LPS-induced extracellular signal-regulated kinase (ERK) activation. In vivo, the intranigral injection of LPS in rats fed a diosgenin-containing diet significantly improved motor dysfunction and reduced TH expression in SN. Conclusion: These results support the effectiveness of diosgenin in protecting dopaminergic neurons from LPS-induced neuroinflammation.     

Histone Methylation Regulation in Neurodegenerative Disorders

Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.     

Microglial Heterogeneity and Its Potential Role in Driving Phenotypic Diversity of Alzheimer’s Disease

Alzheimer’s disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct pro- and/or anti-inflammatory cytokines, potentially affecting the expression of the disease. We carried out a neuropathological and biochemical analysis on a series of AD brain samples, gathering evidence about the heterogeneous involvement of microglia in AD. The neuropathological studies showed differences concerning morphology, density and distribution of microglial cells among AD brains. Biochemical investigations showed increased brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7 and CXCL13 in AD in comparison with control subjects. The molecular profiling achieved by measuring the brain levels of 25 inflammatory factors known to be involved in neuroinflammation allowed a stratification of the AD patients in three distinct “neuroinflammatory clusters”. These findings strengthen the relevance of neuroinflammation in AD pathogenesis suggesting, in particular, that the differential involvement of neuroinflammatory molecules released by microglial cells during the development of the disease may contribute to modulate the characteristics and the severity of the neuropathological changes, driving—at least in part—the AD phenotypic diversity.     

Complement System in Alzheimer’s Disease

Alzheimer’s disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity. Here, we discuss how the complement system is involved in the effective functioning of CNS, while also contributing to chronic neuroinflammation leading to neurodegenerative disorders such as Alzheimer’s disease. We also discuss potential targets in the complement system for stopping its harmful effects via neuroinflammation and provide perspective for the direction of future research in this field.     

Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia

Locus Coeruleus (LC) is the main noradrenergic nucleus of the central nervous system, and its neurons widely innervate the whole brain. LC is severely degenerated both in Alzheimer’s disease (AD) and in Parkinson’s disease (PD), years before the onset of clinical symptoms, through mechanisms that differ among the two disorders. Several experimental studies have shown that noradrenaline modulates neuroinflammation, mainly by acting on microglia/astrocytes function. In the present review, after a brief introduction on the anatomy and physiology of LC, we provide an overview of experimental data supporting a pathogenetic role of LC degeneration in AD and PD. Then, we describe in detail experimental data, obtained in vitro and in vivo in animal models, which support a potential role of neuroinflammation in such a link, and the specific molecules (i.e., released cytokines, glial receptors, including pattern recognition receptors and others) whose expression is altered by LC degeneration and might play a key role in AD/PD pathogenesis. New imaging and biochemical tools have recently been developed in humans to estimate in vivo the integrity of LC, the degree of neuroinflammation, and pathology AD/PD biomarkers; it is auspicable that these will allow in the near future to test the existence of a link between LC-neuroinflammation and neurodegeneration directly in patients.     

Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy

Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.     

The Interplay between Ghrelin and Microglia in Neuroinflammation: Implications for Obesity and Neurodegenerative Diseases

Numerous studies have shown that microglia are capable of producing a wide range of chemokines to promote inflammatory processes within the central nervous system (CNS). These cells share many phenotypical and functional characteristics with macrophages, suggesting that microglia participate in innate immune responses in the brain. Neuroinflammation induces neurometabolic alterations and increases in energy consumption. Microglia may constitute an important therapeutic target in neuroinflammation. Recent research has attempted to clarify the role of Ghre signaling in microglia on the regulation of energy balance, obesity, neuroinflammation and the occurrence of neurodegenerative diseases. These studies strongly suggest that Ghre modulates microglia activity and thus affects the pathophysiology of neurodegenerative diseases. This review aims to summarize what is known from the current literature on the way in which Ghre modulates microglial activity during neuroinflammation and their impact on neurometabolic alterations in neurodegenerative diseases. Understanding the role of Ghre in microglial activation/inhibition regulation could provide promising strategies for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.     

A Sex Perspective in Neurodegenerative Diseases: microRNAs as Possible Peripheral Biomarkers

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.     

A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics

Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative disorders include Alzheimer’s and Parkinson’s disease. Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. This lack of pathogenesis-targeting therapies is primarily due to the restrictive effects of the blood–brain barrier (BBB), which keeps close to 99% of all “foreign substances” out of the brain. Since their discovery, nanoparticles have been successfully used for targeted delivery into many organs, including the brain. This review briefly describes the pathophysiology of Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis, and their current management approaches. We then highlight the major challenges of brain-drug delivery, followed by the role of nanotherapeutics for the diagnosis and treatment of various neurological disorders.     

NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration

Amyloid beta (Aβ)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer’s disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.     

Sequestration of Inflammation in Parkinson’s Disease via Stem Cell Therapy

Parkinson’s disease is the second most common neurodegenerative disease. Insidious and progressive, this disorder is secondary to the gradual loss of dopaminergic signaling and worsening neuroinflammation, affecting patients’ motor capabilities. Gold standard treatment includes exogenous dopamine therapy in the form of levodopa–carbidopa, or surgical intervention with a deep brain stimulator to the subcortical basal ganglia. Unfortunately, these therapies may ironically exacerbate the already pro-inflammatory environment. An alternative approach may involve cell-based therapies. Cell-based therapies, whether endogenous or exogenous, often have anti-inflammatory properties. Alternative strategies, such as exercise and diet modifications, also appear to play a significant role in facilitating endogenous and exogenous stem cells to induce an anti-inflammatory response, and thus are of unique interest to neuroinflammatory conditions including Parkinson’s disease. Treating patients with current gold standard therapeutics and adding adjuvant stem cell therapy, alongside the aforementioned lifestyle modifications, may ideally sequester inflammation and thus halt neurodegeneration.     

Microglia and Alzheimer’s Disease

There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) and neuroinflammation seems to be one of the most fascinating solutions. The primary cell type that performs immunosurveillance and helps clear out unwanted chemicals from the brain is the microglia. Microglia work to reestablish efficiency and stop further degeneration in the early stages of AD but mainly fail in the illness’s later phases. This may be caused by a number of reasons, e.g., a protracted exposure to cytokines that induce inflammation and an inappropriate accumulation of amyloid beta (Aβ) peptide. Extracellular amyloid and/or intraneuronal phosphorylated tau in AD can both activate microglia. The activation of TLRs and scavenger receptors, inducing the activation of numerous inflammatory pathways, including the NF-kB, JAK-STAT, and NLRP3 inflammasome, facilitates microglial phagocytosis and activation in response to these mediators. Aβ/tau are taken up by microglia, and their removal from the extracellular space can also have protective effects, but if the illness worsens, an environment that is constantly inflamed and overexposed to an oxidative environment might encourage continuous microglial activation, which can lead to neuroinflammation, oxidative stress, iron overload, and neurotoxicity. The complexity and diversity of the roles that microglia play in health and disease necessitate the urgent development of new biomarkers that identify the activity of different microglia. It is imperative to comprehend the intricate mechanisms that result in microglial impairment to develop new immunomodulating therapies that primarily attempt to recover the physiological role of microglia, allowing them to carry out their core function of brain protection.     

Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases

The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs—i.e., Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.