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The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer’s disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson’s disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized primarily by a decline in cognitive function. However, the etiopathogenesis of AD is unclear. N6-methyladenosine (m6A) is abundant in the brain, and it is interesting to explore the relationship between m6A and AD causes. In this paper, the gene expression of METTL3 and NDUFA10 were found to correlate with the Mini-mental State Examination (MMSE), which is a clinical indicator of the degree of dementia. METTL3 is involved in post-transcriptional methylation and the formation of m6A. NDUFA10 encodes the protein with NADH dehydrogenase activity and oxidoreductase activity in the mitochondrial electron transport chain. The following three characteristics were observed in this paper: 1. The lower the expression level of NDUFA10, the smaller the MMSE, and the higher the degree of dementia. 2. If the expression level of METTL3 dropped below its threshold, the patient would have a risk of AD with a probability close to 100%, suggesting a basic necessity for m6A to protect mRNA. 3. The lower the expression levels of both METTL3 and NDUFA10, the more likely the patient would suffer from AD, implying the coherence between METTL3 and NDUFA10. Regarding the above discovery, the following hypothesis is presented: METTL3 expression level is downregulated, then the m6A modification level of NDUFA10 mRNA is also decreased, thereby reducing the expression level of NDUFA10-encoded protein. Furthermore, the abnormal expression of NDUFA10 contributes to the assembly disorder of mitochondrial complex I and affects the process of the electron respiratory chain, with the consequent development of AD. In addition, to confirm the above conclusions, the AI Ant Colony Algorithm was improved to be more suitable for discovering the characteristics of AD data, and the SVM diagnostic model was applied to mine the coherent effects on AD between METTL3 and NDUFA10. In conclusion, our findings suggest that dysregulated m6A leads to altered expression of its target genes, thereby affecting AD’s development.

There is a paucity of empirical research on the use of non-pharmacological interventions to both treat and curb the spread of Alzheimer’s disease (AD) across the globe. This paper examines the biochemical and clinical outlook and the social implications of the condition in relation to psychological aspects that may indicate a direction for further interventions. There is a scarcity of research on the effectiveness of using various psychological aspects of AD, a disease characterized by a process of transition from health and independence to a dependent state with a progressive loss of memory and functional skills. The paper investigates the biochemical and psychological aspects of AD and their significance for improving quality of life for patients with this disease. Psychological interventions based on, among other factors, biochemical studies, are conducted to improve the emotional wellbeing of AD patients and may assist in slowing down the progression of the disease. To date, however, no effective methods of AD treatment have been established.

Neurodegenerative diseases (NDs) are a major cause of disability and are related to brain development. The neurological signs of brain lesions can vary from mild clinical shortfalls to more delicate and severe neurological/behavioral symptoms and learning disabilities, which are progressive. In this paper, we have tried to summarize a collective view of various NDs and their possible therapeutic outcomes. These diseases often occur as a consequence of the misfolding of proteins post-translation, as well as the dysfunctional trafficking of proteins. In the treatment of neurological disorders, a challenging hurdle to cross regarding drug delivery is the blood–brain barrier (BBB). The BBB plays a unique role in maintaining the homeostasis of the central nervous system (CNS) by exchanging components between the circulations and shielding the brain from neurotoxic pathogens and detrimental compounds. Here, we outline the current knowledge about BBB deterioration in the evolving brain, its origin, and therapeutic interventions. Additionally, we summarize the physiological scenarios of the BBB and its role in various cerebrovascular diseases. Overall, this information provides a detailed account of BBB functioning and the development of relevant treatments for neurological disorders. This paper will definitely help readers working in the field of neurological scientific communities.

Growing evidence supports the presence of social cognition deficits and social behavior alterations in major and minor neurocognitive disorders (NCDs). Even though the ability to identify socio-emotional changes has significantly improved in recent years, there is still no specific treatment available. Thus, we explored evidence of drug therapies targeting social cognition alterations in NCDs. Papers were selected according to PRISMA guidelines by searching on the PubMed and Scopus databases. Only papers reporting information on pharmacological interventions for the treatment of social cognition and/or social behavioral changes in major and/or minor NCDs were included. Among the 171 articles entered in the paper selection, only 9 papers were eligible for the scope of the review. Trials testing pharmacological treatments for socio-emotional alterations in NCDs are poor and of low-medium quality. A few attempts with neuroprotective, psychoactive, or immunomodulating drugs have been made. Oxytocin is the only drug specifically targeting the social brain that has been tested with promising results in frontotemporal dementia. Its beneficial effects in long-term use have yet to be evaluated. No recommendation can currently be provided. There is a long way to go to identify and test effective targets to treat social cognition changes in NCDs for the ultimate benefit of patients and caregivers.

Alzheimer’s disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly.

Methionine oxidation to the sulfoxide form (MSox) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MSox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MSox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer’s and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MSox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MSox-based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MSox with age as well as neuroinflammatory targets accumulating MSox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MSox-omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases.

Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies to treat Alzheimer’s disease are approved, dozens are in the testing phase, and one was withdrawn, and the other halted, likely due to efficacy issues. However, these outcomes should have been evident since these antibodies cannot enter the brain sufficiently due to the blood–brain barrier (BBB) protectant. However, all products can be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. This paper demonstrates that conjugating with transferrin does not alter the binding to brain proteins such as amyloid-β (Aβ) and α-synuclein. We also present a selection of conjugate designs that will allow cleavage upon entering the brain to prevent their exocytosis while keeping the fragments connected to enable optimal binding to proteins. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively.

Neurodegenerative diseases involve the progressive dysfunction and loss of neurons in the central nervous system and thus present a significant challenge due to the absence of effective therapies for halting or reversing their progression. Based on the characteristics of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which have prolonged incubation periods and protracted courses, exploring non-invasive physical therapy methods is essential for alleviating such diseases and ensuring that patients have an improved quality of life. Photobiomodulation (PBM) uses red and infrared light for therapeutic benefits and functions by stimulating, healing, regenerating, and protecting organizations at risk of injury, degradation, or death. Over the last two decades, PBM has gained widespread recognition as a non-invasive physical therapy method, showing efficacy in pain relief, anti-inflammatory responses, and tissue regeneration. Its application has expanded into the fields of neurology and psychiatry, where extensive research has been conducted. This paper presents a review and evaluation of studies investigating PBM in neurodegenerative diseases, with a specific emphasis on recent applications in AD and PD treatment for both animal and human subjects. Molecular mechanisms related to neuron damage and cognitive impairment are scrutinized, offering valuable insights into PBM’s potential as a non-invasive therapeutic strategy.

Perinatal asphyxia is a complex disease involving massive death of brain cells in full-term newborns. The most impressive consequence of perinatal asphyxia is a neurodegenerative brain injury called hypoxic–ischemic encephalopathy. Management of newborns after perinatal asphyxia is very difficult due to the lack of measurable biomarkers that would be able to assess the severity of the brain injury in the future, help in the selection of therapy, assess the results of treatment and determine the prognosis for the future. Thus, these limitations make long-term neurodevelopmental outcomes unpredictable during life. Quantifying biomarkers that can detect subclinical changes at a stage where routine brain monitoring or imaging is still mute would be a major advance in the care of neonates with brain neurodegeneration after asphyxia. Understanding the effect of perinatal asphyxia on changes in blood neurodegenerative biomarkers over time, which would be commonly used to assess the severity of postpartum encephalopathy, would be an important step in developing precision in predicting the consequences of brain injuries. We urgently need more accurate early predictive markers to guide clinicians when to use neuroprotective therapy. The needed neurodegenerative biomarkers may represent neuronal pathological changes that can be recognized by new technologies such as genomic and proteomic. Nevertheless, the simultaneous blood tau protein and various amyloid changes with the addition of an autophagy marker beclin 1 after perinatal asphyxia have not been studied. We decided to evaluate serum biomarkers of neuronal injury characteristic for Alzheimer’s disease such as amyloid peptides (1-38, 1-40 and 1-42), tau protein and beclin 1, which can predict the progression of brain neurodegeneration in future. In this paper, we report for the first time the significant changes in the above molecules in the blood after asphyxia compared to healthy controls during the 1–7, 8–14 and 15+ days ELISA test.

Alzheimer’s disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aβ amyloid clearance from the brain. However, some recent evidence suggests that astrocytes may play a significant role in the pathogenesis of AD. In this paper, we evaluated the effects of the optogenetic activation of Gq-coupled exogenous receptors expressed in astrocytes as a possible way of restoring brain function in the AD mouse model. We evaluated the effects of the optogenetic activation of astrocytes on long-term potentiation, spinal morphology and behavioral readouts in 5xFAD mouse model of AD. We determined that in vivo chronic activation of astrocytes resulted in the preservation of spine density, increased mushroom spine survival, and improved performance in cognitive behavioral tests. Furthermore, chronic optogenetic stimulation of astrocytes resulted in the elevation of EAAT-2 glutamate uptake transporter expression, which could be a possible explanation for the observed in vivo neuroprotective effects. The obtained results suggest that the persistent activation of astrocytes may be considered a potential therapeutic approach for the treatment of AD and possibly other neurodegenerative disorders.

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early stages of Alzheimer’s disease (AD). Neurophysiological markers such as electroencephalography (EEG) and event-related potential (ERP) are emerging as alternatives to traditional molecular and imaging markers. This paper aimed to review the literature on EEG and ERP markers in individuals with SCD. We analysed 30 studies that met our criteria, with 17 focusing on resting-state or cognitive task EEG, 11 on ERPs, and two on both EEG and ERP parameters. Typical spectral changes were indicative of EEG rhythm slowing and were associated with faster clinical progression, lower education levels, and abnormal cerebrospinal fluid biomarkers profiles. Some studies found no difference in ERP components between SCD subjects, controls, or MCI, while others reported lower amplitudes in the SCD group compared to controls. Further research is needed to explore the prognostic value of EEG and ERP in relation to molecular markers in individuals with SCD.

Alzheimer’s disease and Parkinson’s disease are the two most common neurodegenerative diseases in the world, and their incidence rates are increasing as our society ages. This creates a significant social and economic burden. Although the exact cause and treatment methods for these diseases are not yet known, research suggests that Alzheimer’s disease is caused by amyloid precursor protein, while α-synuclein acts as a causative agent in Parkinson’s disease. The accumulation of abnormal proteins such as these can lead to symptoms such as loss of protein homeostasis, mitochondrial dysfunction, and neuroinflammation, which ultimately result in the death of nerve cells and the progression of neurodegenerative diseases. The medications currently available for these diseases only delay their progression and have many adverse effects, which has led to increased interest in developing natural products with fewer adverse effects. In this study, we selected specific keywords and thesis content to investigate natural products that are effective in treating Alzheimer’s and Parkinson’s diseases. We reviewed 16 papers on natural products and found that they showed promising mechanisms of action such as antioxidant, anti-inflammatory, and mitochondrial function improvement. Other natural products with similar properties could also be considered potential treatments for neurodegenerative diseases, and they can be consumed as part of a healthy diet rather than as medicine.

Early and premature menopause, or premature ovarian insufficiency (POI), affects 1% of women under the age of 40 years. This paper reviews the main aspects of early and premature menopause and their impact on cognitive decline. Based on the literature, cognitive complaints are more common near menopause: a phase marked by a decrease in hormone levels, especially estrogen. A premature reduction in estrogen puts women at a higher risk for cardiovascular disease, parkinsonism, depression, osteoporosis, hypertension, weight gain, midlife diabetes, as well as cognitive disorders and dementia, such as Alzheimer’s disease (AD). Experimental and epidemiological studies suggest that female sex hormones have long-lasting neuroprotective and anti-aging properties. Estrogens seem to prevent cognitive disorders arising from a cholinergic deficit in women and female animals in middle age premature menopause that affects the central nervous system (CNS) directly and indirectly, both transiently and in the long term, leads to cognitive impairment or even dementia, mainly due to the decrease in estrogen levels and comorbidity with cardiovascular risk factors, autoimmune diseases, and aging. Menopausal hormone therapy from menopause to the age of 60 years may provide a “window of opportunity” to reduce the risk of mild cognitive impairment (MCI) and AD in later life. Women with earlier menopause should be taken care of by various specialists such as gynecologists, endocrinologists, neurologists, and psychiatrists in order to maintain their mental health at the highest possible level.

In June 2021, the world was informed about a new drug for Alzheimer’s disease approved by the FDA. Aducanumab (BIIB037, ADU), being a monoclonal antibody IgG1, is the newest AD treatment. The activity of the drug is targeted towards amyloid β, which is considered one of the main causes of Alzheimer’s disease. Clinical trials have revealed time- and dose-dependent activity towards Aβ reduction, as well as cognition improvement. Biogen, the company responsible for conducting research and introducing the drug to the market, presents the drug as a solution to cognitive impairment, but its limitations, costs, and side effects are controversial. The framework of the paper focuses on the mechanism of aducanumab’s action along with the positive and negative sides of the therapy. The review presents the basis of the amyloid hypothesis that is the cornerstone of therapy, as well as the latest information about aducanumab, its mechanism of action, and the possibility of the use of the drug.

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer’s disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the “amyloid hypothesis” that states that the resulting increase in Aβ42:Aβ40 ratio leads to “toxic gain of function” due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that “loss of function” of γ-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40/Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the “loss of γ-secretase function” hypothesis than with the “toxic gain of Aβ42 function” idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, characterised by the accumulation of senile plaques and tau tangles, neurodegeneration, and neuroinflammation in the brain. The development of AD is a pathological cascade starting according to the amyloid hypothesis with the accumulation and aggregation of the β-amyloid peptide (Aβ), which induces hyperphosphorylation of tau and promotes the pro-inflammatory activation of microglia leading to synaptic loss and, ultimately, neuronal death. Modelling AD-related processes is important for both studying the molecular basis of the disease and the development of novel therapeutics. The replication of these processes is often achieved with the use of a purified Aβ peptide. However, Aβ preparations obtained from different sources can have strikingly different properties. This review aims to compare the structure and biological effects of Aβ oligomers and aggregates of a higher order: synthetic, recombinant, purified from cell culture, or extracted from brain tissue. The authors summarise the applicability of Aβ preparations for modelling Aβ aggregation, neurotoxicity, cytoskeleton damage, receptor toxicity in vitro and cerebral amyloidosis, synaptic plasticity disruption, and cognitive impairment in vivo and ex vivo. Further, the paper discusses the causes of the reported differences in the effect of Aβ obtained from the sources mentioned above. This review points to the importance of the source of Aβ for AD modelling and could help researchers to choose the optimal way to model the Aβ-induced abnormalities.

Migraine is a common neurological disorder impairing the quality of life of patients. The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs acting on the central nervous system (CNS). The long-term impact of these medications on cognition and neurodegeneration has never been consistently assessed. The paper reviews pharmacological migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits. These features should be carefully evaluated when prescribing a pharmacological treatment as many migraineurs are of scholar or working age and their performances may be affected by drug misuse. Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results have emerged in the relationship between migraine and dementia, future studies must consider present and past pharmacological regimens as potential confounding factors.

Garlic, Allium sativum, has long been utilized for a number of medicinal purposes around the world, and its medical benefits have been well documented. The health benefits of garlic likely arise from a wide variety of components, possibly working synergistically. Garlic and garlic extracts, especially aged garlic extracts (AGEs), are rich in bioactive compounds, with potent anti-inflammatory, antioxidant and neuroprotective activities. In light of these effects, garlic and its components have been examined in experimental models of Alzheimer’s disease (AD), the most common form of dementia without therapy, and a growing health concern in aging societies. With the aim of offering an updated overview, this paper reviews the chemical composition, metabolism and bioavailability of garlic bioactive compounds. In addition, it provides an overview of signaling mechanisms triggered by garlic derivatives, with a focus on allicin and AGE, to improve learning and memory.

Mercury (Hg) is considered one of the most widespread toxic environmental pollutants, which seems to have multiple effects on organisms even at low concentrations. It has a critical role in many health problems with harmful consequences, with Hg primarily targeting the brain and its components, such as the central nervous system (CNS). Hg exposure was associated with numerous CNS disorders that frequently trigger Alzheimer’s disease (AD). Patients with AD have higher concentrations of Hg in blood and brain tissue. This paper aims to emphasize a correlation between Hg and AD based on the known literature in the occupational field. The outcome shows that all these concerning elements could get attributed to Hg. However, recent studies did not investigate the molecular level of Hg exposure in AD. The present review highlights the interactions between Hg and AD in neuronal degenerations, apoptosis, autophagy, oxidative stress (OS), mitochondrial malfunctions, gastrointestinal (GI) microflora, infertility and altering gene expression.

Neurodegenerative disorders such as Alzheimer’s disease (AD) are distinguished by the irreversible degeneration of central nervous system function and structure. AD is characterized by several different neuropathologies—among others, it interferes with neuropsychiatrical controls and cognitive functions. This disease is the number one neurodegenerative disorder; however, its treatment options are few and, unfortunately, ineffective. In the new strategies devised for AD prevention and treatment, the application of plant-based natural products is especially popular due to lesser side effects associated with their taking. Moreover, their neuroprotective activities target different pathological mechanisms. The current review presents the anti-AD properties of several natural plant substances. The paper throws light on products under in vitro and in vivo trials and compiles information on their mechanism of actions. Knowledge of the properties of such plant compounds and their combinations will surely lead to discovering new potent medicines for the treatment of AD with lesser side effects than the currently available pharmacological proceedings.

Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer’s, and Parkinson’s to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions.

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer’s disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

In developing and developed countries, an increasing elderly population is observed. This affects the growing percentage of people struggling with neurodegenerative diseases, including Alzheimer’s disease. Nevertheless, the pathomechanism of this disease is still unknown. This contributes to problems with early diagnosis of the disease as well as with treatment. One of the most popular hypotheses of Alzheimer’s disease is related to the pathological deposition of amyloid-β (Aβ) in the brain of ill people. In this paper, we discuss issues related to Aβ and its relationship in the development of Alzheimer’s disease. The structure of Aβ and its interaction with the cell membrane are discussed. Not only do the extracellular plaques affect nerve cells, but other forms of this peptide as well.

Alzheimer’s disease (AD) is attracting considerable interest due to its increasing number of cases as a consequence of the aging of the global population. The mainstream concept of AD neuropathology based on pathological changes of amyloid β metabolism and the formation of neurofibrillary tangles is under criticism due to the failure of Aβ-targeting drug trials. Recent findings have shown that AD is a highly complex disease involving a broad range of clinical manifestations as well as cellular and biochemical disturbances. The past decade has seen a renewed importance of metabolic disturbances in disease-relevant early pathology with challenging areas in establishing the role of local micro-fluctuations in glucose concentrations and the impact of insulin on neuronal function. The role of the S100 protein family in this interplay remains unclear and is the aim of this research. Intracellularly the S100B protein has a protective effect on neurons against the toxic effects of glutamate and stimulates neurites outgrowth and neuronal survival. At high concentrations, it can induce apoptosis. The aim of our study was to extend current knowledge of the possible impact of hyper-glycemia and -insulinemia directly on neuronal S100B secretion and comparison to oxidative stress markers such as ROS, NO and DBSs levels. In this paper, we have shown that S100B secretion decreases in neurons cultured in a high-glucose or high-insulin medium, while levels in cell lysates are increased with statistical significance. Our findings demonstrate the strong toxic impact of energetic disturbances on neuronal metabolism and the potential neuroprotective role of S100B protein.

Currently, there is no cure for Alzheimer’s disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A β peptides that regulate several key physiological brain processes, and the incomplete understanding of AD′s aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation. Hexokinase (HK) is the key enzyme of glucose metabolism and is associated with mitochondria to exert its function. Recent studies have demonstrated that the dissociation of HK from mitochondria is enough to activate the NOD-like receptor protein 3 (NLRP3) inflammasome and leads to the release of interleukin-1β (IL-1β). However, the effect of increased IL-1β on the expression of HK is still unclear in AD. In this paper, we used positron emission tomography (PET), Western blotting and immunofluorescence to study the glucose metabolism, and the expression and distribution of HK in AD. Furthermore, we used lipopolysaccharide (LPS), nigericin (Nig), CY-09 and lonidamine (LND) to treat N2a and N2a-sw cells to investigate the link between IL-1β and HK in AD. The results show decreased expression of HK and the dissociation of HK from mitochondria in AD. Furthermore, a reduction of the expression of IL-1β could increase the expression of HK in AD. These results suggest that inhibiting inflammation may help to restore glucose metabolism in AD.

Neurodegeneration is the pathological condition, in which the nervous system or neuron loses its structure, function, or both, leading to progressive degeneration or the death of neurons, and well-defined associations of tissue system, resulting in clinical manifestations. Neuroinflammation has been shown to precede neurodegeneration in several neurodegenerative diseases (NDs). No drug is yet known to delay or treat neurodegeneration. Although the etiology and potential causes of NDs remain widely indefinable, matrix metalloproteinases (MMPs) evidently have a crucial role in the progression of NDs. MMPs, a protein family of zinc (Zn2+)-containing endopeptidases, are pivotal agents that are involved in various biological and pathological processes in the central nervous system (CNS). The current review delineates the several emerging evidence demonstrating the effects of MMPs in the progression of NDs, wherein they regulate several processes, such as (neuro)inflammation, microglial activation, amyloid peptide degradation, blood brain barrier (BBB) disruption, dopaminergic apoptosis, and α-synuclein modulation, leading to neurotoxicity and neuron death. Published papers to date were searched via PubMed, MEDLINE, etc., while using selective keywords highlighted in our manuscript. We also aim to shed a light on pathophysiological effect of MMPs in the CNS and focus our attention on its detrimental and beneficial effects in NDs, with a special focus on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS), and Huntington’s disease (HD), and discussed various therapeutic strategies targeting MMPs, which could serve as potential modulators in NDs. Over time, several agents have been developed in order to overcome challenges and open up the possibilities for making selective modulators of MMPs to decipher the multifaceted functions of MMPs in NDs. There is still a greater need to explore them in clinics.

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients’ needs to be accomplished first to meet this aim.

Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.

The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.

Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by β-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 μM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the β-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE−/−) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD.

Neurons are extremely vulnerable cells that tightly rely on the brain’s highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer’s disease (AD).

Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders related to aging. Though several risk factors are shared between these two diseases, the exact relationship between them is still unknown. In this paper, we analyzed how these two diseases relate to each other from the genomic, epigenomic, and transcriptomic viewpoints. Using an extensive literature mining, we first accumulated the list of genes from major genome-wide association (GWAS) studies. Based on these GWAS studies, we observed that only one gene (HLA-DRB5) was shared between AD and PD. A subsequent literature search identified a few other genes involved in these two diseases, among which SIRT1 seemed to be the most prominent one. While we listed all the miRNAs that have been previously reported for AD and PD separately, we found only 15 different miRNAs that were reported in both diseases. In order to get better insights, we predicted the gene co-expression network for both AD and PD using network analysis algorithms applied to two GEO datasets. The network analysis revealed six clusters of genes related to AD and four clusters of genes related to PD; however, there was very low functional similarity between these clusters, pointing to insignificant similarity between AD and PD even at the level of affected biological processes. Finally, we postulated the putative epigenetic regulator modules that are common to AD and PD.

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting the harmful effects of free radicals. The GLP-1R expression has been reported in the cerebral cortex, especially occipital and frontal lobes, the hypothalamus, and the thalamus. Liraglutide reduced the area of ischemia caused by MCAO (middle cerebral artery occlusion), limited neurological deficits, decreased hyperglycemia caused by stress, and presented anti-apoptotic effects by increasing the expression of Bcl-2 and Bcl-xl proteins and reduction of Bax and Bad protein expression. The pharmaceutical managed to decrease concentrations of proapoptotic factors, such as NF-κB (Nuclear Factor-kappa β), ICAM-1 (Intercellular Adhesion Molecule 1), caspase-3, and reduced the level of TUNEL-positive cells. Liraglutide was able to reduce the level of free radicals by decreasing the level of malondialdehyde (MDA), and increasing the superoxide dismutase level (SOD), glutathione (GSH), and catalase. Liraglutide may affect the neurovascular unit causing its remodeling, which seems to be crucial for recovery after stroke. Liraglutide may stabilize atherosclerotic plaque, as well as counteract its early formation and further development. Liraglutide, through its binding to GLP-1R (glucagon like peptide-1 receptor) and consequent activation of PI3K/MAPK (Phosphoinositide 3-kinase/mitogen associated protein kinase) dependent pathways, may have a positive impact on Aβ (amyloid beta) trafficking and clearance by increasing the presence of Aβ transporters in cerebrospinal fluid. Liraglutide seems to affect tau pathology. It is possible that liraglutide may have some stem cell stimulating properties. The effects may be connected with PKA (phosphorylase kinase A) activation. This paper presents potential mechanisms of liraglutide activity in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

Vitamin E was proposed as treatment for Alzheimer’s disease many years ago. However, the effectiveness of the drug is not clear. Vitamin E is an antioxidant and neuroprotector and it has anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer’s disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer’s. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer’s disease? In this paper we review the studies with and without positive results in Alzheimer’s disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not.

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is an important part of the cholinergic nerve system in the brain. Moreover, it is associated with a cholinergic anti-inflammatory pathway in the termination of the parasympathetic nervous system. Antagonists of α7 nAChR are a wide group represented by conotoxin and bungarotoxin. Even Alzheimer’s disease drug memantine acting as an antagonist in its side pathway belongs in this group. Agonists of α7 nAChR are suitable for treatment of multiple cognitive dysfunctions such as Alzheimer’s disease or schizophrenia. Inflammation or even sepsis can be ameliorated by the agonistic acting compounds. Preparations RG3487, SEN34625/WYE-103914, SEN12333, ABT-107, Clozapine, GTS-21, CNI-1493, and AR-R17779 are representative examples of the novel compounds with affinity toward the α7 nAChR. Pharmacological, toxicological, and medicinal significance of α7 nAChR are discussed throughout this paper.

It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients’ brain composed of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aβ and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AβOs) aggregation in the pathogenesis of AD. Moreover, binding of AβOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AβO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aβ oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AβO receptors related to toxic activity of oligomers.