Pathogenesis Of Neurodegenerative Disorders Research Articles

NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.

The NADPH oxidase (NOX) enzyme family, located in the central nervous system (CNS), is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and Stroke. Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics.

α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies.

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.

The role of Nrf2 signaling pathways in nerve damage repair.

The protein, Nuclear factor-E2-related factor 2 (Nrf2), is a transitory protein that acts as a transcription factor and is involved in the regulation of many cytoprotective genes linked to xenobiotic metabolism and antioxidant responses. Based on the existing clinical and experimental data, it can be inferred that neurodegenerative diseases are characterized by an excessive presence of markers of oxidative stress (OS) and a reduced presence of antioxidant defense systems in both the brain and peripheral tissues. The presence of imbalances in the homeostasis between oxidants and antioxidants has been recognized as a substantial factor in the pathogenesis of neurodegenerative disorders. The dysregulations include several cellular processes such as mitochondrial failure, protein misfolding, and neuroinflammation. These dysregulations all contribute to the disruption of proteostasis in neuronal cells, leading to their eventual mortality. A noteworthy component of Nrf2, as shown by recent research undertaken over the last decade, is to its role in the development of resistance to OS. Nrf2 plays a pivotal role in regulating systems that defend against OS. Extant research offers substantiation for the protective and defensive roles of Nrf2 in the context of neurodegenerative diseases. The purpose of this study is to provide a comprehensive analysis of the influence of Nrf2 on OS and its function in regulating antioxidant defense systems within the realm of neurodegenerative diseases. Furthermore, we evaluate the most recent academic inquiries and empirical evidence about the beneficial and potential role of certain Nrf2 activator compounds within the realm of therapeutic interventions.

Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.

Gut-Brain Axis Deregulation and Its Possible Contribution to Neurodegenerative Disorders.

The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.

Top/Middle-Down Characterization of α-Synuclein Glycoforms.

α-Synuclein is an intrinsically disordered protein that plays a critical role in the pathogenesis of neurodegenerative disorders, such as Parkinson's disease. Proteomics studies of human brain samples have associated the modification of the O-linked N-acetyl-glucosamine (O-GlcNAc) to several synucleinopathies; in particular, the position of the O-GlcNAc can regulate protein aggregation and subsequent cell toxicity. There is a need for site specific O-GlcNAc α-synuclein screening tools to direct better therapeutic strategies. In the present work, for the first time, the potential of fast, high-resolution trapped ion mobility spectrometry (TIMS) preseparation in tandem with mass spectrometry assisted by an electromagnetostatic (EMS) cell, capable of electron capture dissociation (ECD), and ultraviolet photodissociation (213 nm UVPD) is illustrated for the characterization of α-synuclein positional glycoforms: T72, T75, T81, and S87 modified with a single O-GlcNAc. Top-down 213 nm UVPD and ECD MS/MS experiments of the intact proteoforms showed specific product ions for each α-synuclein glycoforms associated with the O-GlcNAc position with a sequence coverage of ∼68 and ∼82%, respectively. TIMS-MS profiles of α-synuclein and the four glycoforms exhibited large structural heterogeneity and signature patterns across the 8+-15+ charge state distribution; however, while the α-synuclein positional glycoforms showed signature mobility profiles, they were only partially separated in the mobility domain. Moreover, a middle-down approach based on the Val40-Phe94 (55 residues) chymotrypsin proteolytic product using tandem TIMS-q-ECD-TOF MS/MS permitted the separation of the parent positional isomeric glycoforms. The ECD fragmentation of the ion mobility and m/z separated isomeric Val40-Phe94 proteolytic peptides with single O-GlcNAc in the T72, T75, T81, and S87 positions provided the O-GlcNAc confirmation and positional assignment with a sequence coverage of ∼80%. This method enables the high-throughput screening of positional glycoforms and further enhances the structural mass spectrometry toolbox with fast, high-resolution mobility separations and 213 nm UVPD and ECD fragmentation capabilities.

CNS-Active p38α MAPK Inhibitors for the Management of Neuroinflammatory Diseases: Medicinal Chemical Properties and Therapeutic Capabilities.

During the last two decades, many p38α mitogen-activated protein kinase (p38α MAPK) inhibitors have been developed and tested in preclinical/clinical studies for the treatment of various disorders, especially problems with the origin of inflammation. Previous studies strongly suggest the involvement of the p38α MAPK pathway in the pathogenesis of neurodegenerative disorders. Despite the significant progress made in this field, so far no studies have focused on p38α MAPK inhibitors that have the capability to be used for the treatment of neurodegenerative disorders. In the present review, we evaluated a wide range of well-known p38α MAPK inhibitors (more than 140 small molecules) by measuring key physicochemical parameters to identify those capable of successfully crossing the blood-brain barrier (BBB). As a result, we identify about 50 naturally occurring and synthetic p38α MAPK inhibitors with high potential to cross the BBB, which can be further explored in the future for the treatment of neurodegenerative disorders. In addition, a detailed analysis of the previously released X-ray crystal structure of the inhibitors in the active site of the p38α MAPK enzyme revealed that some residues such as Met109 play a critical role in the occurrence of effective interactions by constructing strong H-bonds. This study can encourage scientists to focus more on the design, production, and biological evaluation of new central nervous system (CNS)-active p38α MAPK inhibitors in the future.

Brain-inhabiting bacteria and neurodegenerative diseases: the “brain microbiome” theory

Controversies surrounding the validity of the toxic proteinopathy theory of Alzheimer’s disease have led the scientific community to seek alternative theories in the pathogenesis of neurodegenerative disorders (ND). Recent studies have provided evidence of a microbiome in the central nervous system. Some have hypothesized that brain-inhabiting organisms induce chronic neuroinflammation, leading to the development of a spectrum of NDs. Bacteria such as Chlamydia pneumoniae, Helicobacter pylori, and Cutibacterium acnes have been found to inhabit the brains of ND patients. Furthermore, several fungi, including Candida and Malassezia species, have been identified in the central nervous system of these patients. However, there remains several limitations to the brain microbiome hypothesis. Varying results across the literature, concerns regarding sample contamination, and the presence of exogenous deoxyribonucleic acids have led to doubts about the hypothesis. These results provide valuable insight into the pathogenesis of NDs. Herein, we provide a review of the evidence for and against the brain microbiome theory and describe the difficulties facing the hypothesis. Additionally, we define possible mechanisms of bacterial invasion of the brain and organism-related neurodegeneration in NDs and the potential therapeutic premises of this theory.

Extracellular Vesicles in Neurodegenerative Diseases: An Update.

Neurodegenerative diseases affect millions of people worldwide. The likelihood of developing a neurodegenerative disease rises dramatically as life expectancy increases. Although it has drawn significant attention, there is still a lack of proper effective treatments for neurodegenerative disease because the mechanisms of its development and progression are largely unknown. Extracellular vesicles (EVs) are small bi-lipid layer-enclosed nanosized particles in tissues and biological fluids. EVs are emerging as novel intercellular messengers and regulate a series of biological responses. Increasing evidence suggests that EVs are involved in the pathogenesis of neurodegenerative disorders. In this review, we summarize the recent findings of EVs in neurodegenerative diseases and bring up the limitations in the field.

Increased Serum Levels of IL-1β after Ischemic Stroke are Inversely Associated with Vitamin D.

The initial inflammatory reaction starts following occlusion in ischemic stroke (IS). Interleukin-1β (IL-1β) is a pro-inflammatory cytokine with a crucial role in the pathogenesis of neurodegenerative disorders. To investigate the levels of IL-1β and vitamin D (VitD) in patients with IS compared with controls and their correlation. The serum level of 25-OH VitD and IL-1β was assessed in 102 IS patients (0-24 h after stroke) and 102 controls with an enzyme-linked immunosorbent assay (ELISA) kit. We found a significant increase in IL-1β (80.14±6.8 vs. 60.32±4.1 pg/ml, p<0.05) and a decrease in VitD level (24.3±1.4 vs. 29.9±1.5 ng/ml, p<0.01) in the IS patients compared with the controls. There was a significantly positive correlation between the National Institutes of Health Stroke Scale (NIHSS) and IL-1β according to both the Spearman correlation (r=0.35, p=0.0003) and the linear regression (beta=0.255, p=0.014). Also, a significant negative association between VitD and NIHSS was detected by the Spearman correlation (r=-0.41, p<0.0001) and the linear regression (beta=-0.381, p=0.000). Moreover, we found a significant negative correlation (r=-0.26, p=0.006) between the serum levels of VitD and IL-1β in the patient group. Ischemic stroke correlates positively with IL-1β and negatively with VitD levels. The speculated role of VitD deficiency in the evolution and severity of stroke may be justified by its role in the modification of inflammation.

Dopamine Activates the D1R-Zn2+ Signaling Pathway to Trigger Inflammatory Response in Primary-Cultured Rat Embryonic Cortical Neurons.

Neuroinflammation is an early event during the pathogenesis of neurodegenerative disorders. Most studies focus on how the factors derived from pathogens or tissue damage activate the inflammation-pyroptosis cell death pathway. It is unclear whether endogenous neurotransmitters could induce inflammatory responses in neurons. Our previous reports have shown that dopamine-induced elevation of intracellular Zn2+ concentration via the D1-like receptor (D1R) is a prerequisite for autophagy and cell death in primary cultured rat embryonic neurons. Here we further examined that this D1R-Zn2+ signaling initiates the transient inflammatory response leading to cell death in cultured cortical neurons. Pretreating the cultured neurons with Zn2+ chelator and inhibitors against inflammation could enhance the cell viability in neurons treated with dopamine and dihydrexidine, an agonist of D1R. Both dopamine and dihydrexidine greatly enhanced inflammasome formation; a Zn2+ chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine, suppressed this increment. Dopamine and dihydrexidine increased the expression levels of NOD-like receptor pyrin domain-containing protein 3 and enhanced the maturation of caspase-1, gasdermin D, and IL-1β; these changes were all Zn2+-dependent. Dopamine treatment did not recruit the N-terminal of the gasdermin D to the plasma membrane but enhanced its localization to the autophagosomes. Pretreating the neurons with IL-1β could increase the viability of neurons challenged with dopamine. These results demonstrate a novel D1R-Zn2+ signaling cascade activating neuroinflammation and cell death. Therefore, maintaining a balance between dopamine homeostasis and inflammatory responses is an important therapeutic target for neurodegeneration. Dopamine elicits transient inflammatory responses in cultured cortical neurons via the D1R-Zn2+ signaling pathway. Dopamine elevates [Zn2+]i to induce the formation of inflammasomes, which activates caspase-1, resulting in the maturation of IL-1β and gasdermin D (GSDMD). Therefore, the homeostasis of dopamine and Zn2+ are critical therapeutic targets for inflammation-derived neurodegeneration.

TREM2 expression on the microglia resolved lead exposure-induced neuroinflammation by promoting anti-inflammatory activities

Neurotoxicity caused by environmental lead (Pb) pollution is a worldwide public health concern, and developing a therapeutic strategy against Pb-induced neurotoxicity is an important area in the current research. Our prior research has demonstrated the significant involvement of microglia-mediated inflammatory responses in the manifestation of Pb-induced neurotoxicity. Additionally, the suppression of proinflammatory mediator activity significantly mitigated the toxic effects associated with Pb exposure. Recent studies have highlighted the critical role of the triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of neurodegenerative disorders. TREM2 exerted protective effects on inflammation, but whether TREM2 is involved in Pb-induced neuroinflammation is poorly understood. In the present study, cell culture experiments and animal models were designed to investigate the role of TREM2 in Pb’s neuroinflammation. We examined the impact of pro- and anti-inflammatory cytokines involved in Pb-induced neuroinflammation. Flow cytometry and microscopy techniques were applied to detect microglia phagocytosis and migration ability. Our results showed that Pb treatment significantly downregulated TREM2 expression and altered the localization of TREM2 expression in microglia. The protein expression of TREM2 was restored, and the inflammatory responses provoked by Pb exposure were ameliorated upon the overexpression of TREM2. Furthermore, the phagocytosis and migratory capabilities of microglia, which were impaired due to Pb exposure, were alleviated by TREM2 overexpression. Our in vitro findings were corroborated in vivo, demonstrating that TREM2 regulates the anti-inflammatory functions of microglia, thereby mitigating Pb-induced neuroinflammation. Our results provide insights into the detailed mechanism by which TREM2 alleviates Pb-induced neuroinflammation and suggest that activating the anti-inflammatory functions of TREM2 may represent a potential therapeutic strategy against environmental Pb-induced neurotoxicity.

New Directions to Approach Oxidative Stress Related to Physical Activity and Nutraceuticals in Normal Aging and Neurodegenerative Aging.

Oxidative stress (OS) plays, perhaps, the most important role in the advanced aging process, cognitive impairment and pathogenesis of neurodegenerative disorders. The process generates tissue damage via specific mechanisms on proteins, lipids and nucleic acids of the cells. An imbalance between the excessive production of oxygen- and nitrogen-reactive species and antioxidants leads to a progressive decline in physiological, biological and cognitive functions. Accordingly, we need to design and develop favourable strategies for stopping the early aging process as well as the development of neurodegenerative diseases. Exercise training and natural or artificial nutraceutical intake are considered therapeutic interventions that reduce the inflammatory process, increase antioxidant capacities and promote healthy aging by decreasing the amount of reactive oxygen species (ROS). The aim of our review is to present research results in the field of oxidative stress related to physical activity and nutraceutical administration for the improvement of the aging process, but also related to reducing the neurodegeneration process based on analysing the beneficial effects of several antioxidants, such as physical activity, artificial and natural nutraceuticals, as well as the tools by which they are evaluated. In this paper, we assess the recent findings in the field of oxidative stress by analysing intervention antioxidants, anti-inflammatory markers and physical activity in healthy older adults and the elderly population with dementia and Parkinson's disease. By searching for studies from the last few years, we observed new trends for approaching the reduction in redox potential using different tools that evaluate regular physical activity, as well as antioxidant and anti-inflammatory markers preventing premature aging and the progress of disabilities in neurodegenerative diseases. The results of our review show that regular physical activity, supplemented with vitamins and oligomolecules, results in a decrease in IL-6 and an increase in IL-10, and has an influence on the oxidative metabolism capacity. In conclusion, physical activity provides an antioxidant-protective effect by decreasing free radicals and proinflammatory markers.

Chitinase Signature in the Plasticity of Neurodegenerative Diseases.

Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

Activators of Nrf2 to Counteract Neurodegenerative Diseases

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to oxidative damage. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is strictly related to anti-inflammatory and antioxidative cell response; therefore, its activation and the consequent enhancement of the related cellular pathways have been proposed as a potential therapeutic approach. Several Nrf2 activators with different mechanisms and diverse structures have been reported, but those applied for neurodisorders are still limited. However, in the very last few years, interesting progress has been made, particularly in enhancing the blood-brain barrier penetration, to make Nrf2 activators effective drugs, and in designing Nrf2-based multitarget-directed ligands to affect multiple pathways involved in the pathology of neurodegenerative diseases. The present review gives an overview of the most representative findings in this research area.

Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders-An Overview.

Nitric oxide, a ubiquitous molecule found throughout the natural world, is a key molecule implicated in many central and benefic molecular pathways and has a well-established role in the function of the central nervous system, as numerous studies have previously shown. Dysregulation of its metabolism, mainly the upregulation of nitric oxide production, has been proposed as a trigger and/or aggravator for many neurological affections. Increasing evidence supports the implication of this molecule in prevalent neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. The mechanisms proposed for its neurotoxicity mainly center around the increased quantities of nitric oxide that are produced in the brain, their cause, and, most importantly, the pathological metabolic cascades created. These cascades lead to the formation of neuronal toxic substances that impair the neurons' function and structure on multiple levels. The purpose of this review is to present the main causes of increased pathological production, as well as the most important pathophysiological mechanisms triggered by nitric oxide, mechanisms that could help explain a part of the complex picture of neurodegenerative diseases and help develop targeted therapies.

Fecal microbiota transplantation in Parkinson's disease-A randomized repeat-dose, placebo-controlled clinical pilot study.

The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease. This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months). Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group. Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms. ClinicalTrial.gov, identifier: NCT03671785.

Chapter 3 - Pathology vs pathogenesis: Rationale and pitfalls in the clinicopathology model of neurodegeneration

In neurodegenerative disorders, the term pathology is often implicitly referred to as pathogenesis. Pathology has been conceived as a window into the pathogenesis of neurodegenerative disorders. This clinicopathologic framework posits that what can be identified and quantified in postmortem brain tissue can explain both premortem clinical manifestations and the cause of death, a forensic approach to understanding neurodegeneration. As the century-old clinicopathology framework has yielded little correlation between pathology and clinical features or neuronal loss, the relationship between proteins and degeneration is ripe for revisitation. There are indeed two synchronous consequences of protein aggregation in neurodegeneration: the loss of the soluble/normal proteins on one; the accrual of the insoluble/abnormal fraction of these proteins on the other. The omission of the first part in the protein aggregation process is an artifact of the early autopsy studies: soluble, normal proteins have disappeared, with only the remaining insoluble fraction amenable to quantification. We here review the collective evidence from human data suggesting that protein aggregates, known collectively as pathology, are the consequence of many biological, toxic, and infectious exposures, but may not explain alone the cause or pathogenesis of neurodegenerative disorders.

Chronic Neuroinflammation Induced by Systemic Administration of Lipopolysaccharide Leads to Behavioral Impairments in Mice

Background: There is evidence that chronic neuroinflammation is involved in the pathogenesis of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. In this regard, animal models are considered important tools for the study of neuroinflammation associated with these diseases. The injection of lipopolysaccharide (LPS) is the most commonly used approach for inducing neuroinflammation in animal models. However, there are limited and inconsistent studies regarding the effect of the chronic administration of LPS on behavioral parameters. Accordingly, this experimental study aimed to compare the effect of the chronic injection of LPS in two different doses on behavioral alterations, including spatial learning and working memory in mice. Methods: Thirty-six male BALB/c mice were used in this study. After acclimatization for a week, mice were randomly divided into three groups. Control mice were intraperitoneally (IP) injected with saline for seven consecutive days, and mice of the second group received 250 μg/kg LPS (IP) dissolved in saline for a week. Finally, mice of the third group were administered 750 μg/kg LPS (IP) dissolved in saline for a week. Morris water maze (MWM) and Y-maze were performed to assess spatial learning and working memory alterations in treated mice, respectively. Results: It was found that LPS treatment with a high dose (750 μg/kg) results in working memory impairment (P=0.0024) and cognitive dysfunction (P=0.0030) based on Y-maze and MWM test results. Conclusion: Our findings suggest that the LPS-induced model of chronic neuroinflammation can be used as an important tool for the investigation of the pathomechanisms of neurodegenerative disorders and the development of new pharmacotherapeutic options.

Preventive Effect of Saccharomyces boulardii on Memory Impairment Induced by Lipopolysaccharide in Rats.

Recent studies have indicated that dysfunction of gut microbiota, living microorganisms of the digestive tract, plays a role in the pathogenesis of neurodegenerative disorders, indicating the valuable impact of probiotics as a potential preventive or therapeutic strategy. Saccharomyces boulardii is a yeast probiotic with beneficial effects on various disorders, ranging from inflammatory gastrointestinal diseases to brain and behavioral disorders. Herein, we examined the effect of S. boulardii on memory impairment induced by lipopolysaccharide (LPS) in Wistar rats. Four groups of rats were used in this study (N = 10): (1) control [Cnt], (2) LPS, (3) LPS + S. boulardii [LPS + S], and (4) S. boulardii [S]. Animals were orally administered S. boulardii (250 mg/rat) or saline by gavage for 4 weeks. From the 14th day of the study, animals were administered intraperitoneal LPS (0.25 mg/kg/day) or saline for 9 days. We assessed memory impairment, neuroinflammation, and amyloid-β deposition. S. boulardii ameliorated LPS-induced memory dysfunction. We observed that S. boulardii significantly reduced the elevated levels of serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, as well as hippocampal levels of NLRP3 and caspase-1 in the LPS model. Moreover, S. boulardii alleviated amyloid-β deposition in the rat hippocampus. Collectively, our findings indicated that S. boulardii could inhibit memory impairment, neuroinflammation, and amyloid-β accumulation induced by LPS, possibly by modifying the gut microbiota.