Chronic Neurodegenerative Disorders Research Articles

Blood-Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder.

Major depression represents a complex and prevalent psychological disease that is characterized by persistent depressed mood, impaired cognitive function and complicated pathophysiological and neuroendocrine alterations. Despite the multifactorial etiology of depression, one of the most recent factors to be identified as playing a critical role in the development of depression is blood-brain barrier (BBB) disruption. The occurrence of BBB integrity disruption contributes to the disturbance of brain homeostasis and leads to complications of neurological diseases, such as stroke, chronic neurodegenerative disorders, neuroinflammatory disorders. Recently, BBB associated tight junction disruption has been shown to implicate in the pathophysiology of depression and contribute to increased susceptibility to depression. However, the underlying mechanisms and importance of BBB damage in depression remains largely unknown. This review highlights how BBB disruption regulates the depression process and the possible molecular mechanisms involved in development of depression-induced BBB dysfunction. Moreover, insight on promising therapeutic targets for treatment of depression with associated BBB dysfunctions are also discussed.

Risk factors for hyperthermia mortality among emergency department patients

PurposeThis study examines risk factors for heat-related mortality due to hyperthermia in emergency department patients, a vulnerable population. MethodsThis matched case-control study used statewide, longitudinally linked emergency department (ED) data and death records from California. Cases comprised California residents (≥18 years) who presented to a state-licensed ED and died of hyperthermia during the study period (2009–2012). For each case, up to five ED patients were randomly selected as live controls and matched on sex and age. Patients’ demographic characteristics and history of ED utilization for alcohol use, drug use, psychiatric disorders, heart-related conditions, chronic respiratory disease, neurodegenerative disorders, and cerebrovascular disease were assessed in relationship to hyperthermia mortality. ResultsUsing multivariate conditional logistic regression models, hyperthermia mortality cases had higher odds of prior ED utilization for alcohol use (OR = 11.16, 95% CI = 3.87, 32.17) compared to controls. Cases were also more likely than controls to have Medicare insurance (OR = 5.80, 95% CI = 1.70, 15.15) or self-pay (OR = 5.39, 95% CI = 1.73, 16.79), at their most recent ED visit. ConclusionsED patients presenting with alcohol problems may face increased risk of hyperthermia mortality. To help reduce heat-related mortality, EDs should consider interventions that target patients vulnerable to heat exposure.

Unravelling the potential neuroprotective facets of erythropoietin for the treatment of Alzheimer's disease.

During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

The Origins of the Protein Spread in Parkinson's Disease.

The Origins of the Protein Spread in Parkinson's Disease.

Recent advances with liposomes as drug carriers for treatment of neurodegenerative diseases.

A major challenge in treating neurogenerative diseases is delivering drugs across the blood-brain barrier (BBB). In this review, we summarized the development of liposome-based drug delivery system with enhanced BBB penetration for efficient brain drug delivery. We focused on the liposome-based therapeutics targeting Alzheimer's disease and Parkinson's disease because they are most common types of adult chronic neurodegenerative disorders. A variety of liposome with surface modification of BBB-targeting ligands have been created to cross the BBB via transcytosis to the therapeutic efficacy of Alzheimer's disease and Parkinson's disease drugs. Recent advances in liposome are providing alternatives to overcome BBB for more efficient therapeutic strategy. To improve the BBB penetration of liposomes, we need to completely understand the pathophysiological changes at the BBB.

The CXCL12/CXCR4/ACKR3 Response Axis in Chronic Neurodegenerative Disorders of the Central Nervous System: Therapeutic Target and Biomarker.

There has been an increase in the incidence of chronic neurodegenerative disorders of the central nervous system, including Alzheimer's and Parkinson's diseases, over the recent years mostly due to the rise in the number of elderly individuals. In addition, various neurodegenerative disorders are related to imbalances in the CXCL12/CXCR4/ACKR3 response axis. Notably, the CXC Chemokine Ligand 12 (CXCL12) is essential for the development of the central nervous system. Moreover, the expression and distribution of CXCL12 and its receptors are associated with the aggravation or alleviation of symptoms of neurodegenerative disorders. Therefore, the current review sought to highlight the specific functions of CXCL12 and its receptors in various neurodegenerative disorders, in order to provide new insights for future research.

From Brain Organoids to Networking Assembloids: Implications for Neuroendocrinology and Stress Medicine.

Brain organoids are three-dimensional cultures that contain multiple types of cells and cytoarchitectures, and resemble fetal human brain structurally and functionally. These organoids are being used increasingly to model brain development and disorders, however, they only partially recapitulate such processes, because of several limitations, including inability to mimic the distinct cortical layers, lack of functional neuronal circuitry as well as non-neural cells and gyrification, and increased cellular stress. Efforts to create improved brain organoid culture systems have led to region-specific organoids, vascularized organoids, glia-containing organoids, assembloids, sliced organoids and polarized organoids. Assembloids are fused region-specific organoids, which attempt to recapitulate inter-regional and inter-cellular interactions as well as neural circuitry development by combining multiple brain regions and/or cell lineages. As a result, assembloids can be used to model subtle functional aberrations that reflect complex neurodevelopmental, neuropsychiatric and neurodegenerative disorders. Mammalian organisms possess a highly complex neuroendocrine system, the stress system, whose main task is the preservation of systemic homeostasis, when the latter is threatened by adverse forces, the stressors. The main central parts of the stress system are the paraventricular nucleus of the hypothalamus and the locus caeruleus/norepinephrine-autonomic nervous system nuclei in the brainstem; these centers innervate each other and interact reciprocally as well as with various other CNS structures. Chronic dysregulation of the stress system has been implicated in major pathologies, the so-called chronic non-communicable diseases, including neuropsychiatric, neurodegenerative, cardiometabolic and autoimmune disorders, which lead to significant population morbidity and mortality. We speculate that brain organoids and/or assembloids could be used to model the development, regulation and dysregulation of the stress system and to better understand stress-related disorders. Novel brain organoid technologies, combined with high-throughput single-cell omics and gene editing, could, thus, have major implications for precision medicine.

Influence of Trace Elements on Neurodegenerative Diseases of The Eye-The Glaucoma Model.

Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.

Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human superoxide dismutase-1 gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38–38.5 °C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36–36.5 °C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on/12-off or 24 h-on/24 h-off) to lower body temperature (1–3 °C). Cooled ALS mice showed a significant delay in disease onset (103–112 days) compared to normothermia mice (80–90 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 ± 7 days) compared to normothermic mice (135 ± 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria.

Trichilia catigua and Turnera diffusa extracts: In vitro inhibition of tyrosinase, antiglycation activity and effects on enzymes and pathways engaged in the neuroinflammatory process

Ethnopharmacological relevanceFlavonoids interact with multiple targets in Central Nervous System resulting in a broad neuroprotection mediated by complementary processes and synergic interactions. Therefore, flavonoid-based therapies may input positive outcomes in the prevention and early management of neurodegenerative diseases. In Brazilian folk medicine Trichilia catigua is used for its neuroactive properties, such as neurostimulant, antioxidant and anti-neuroinflammatory, while Turnera diffusa is traditionally used as a tonic in neurasthenia. Both species are known to be rich in flavonoids. Aim of the studyTo study aqueous extracts of T. catigua and T. diffusa in terms of their antioxidant and antiglycation effects, inhibition of tyrosinase activity, and interaction with enzymes and pathways engaged in neuroinflammation. Moreover, whenever possible, to establish a relationship between the studied activities and the traditional usage of the species. Materials and methodsThe phenolic profiles of the aqueous extracts were validated by HPLC-DAD. The effect of the extracts over mushroom tyrosinase and 5-lipoxygenase activities, as well as their capacity to impair bovine serum albumin glycation, were assessed by in vitro assays. The anti-neuroinflammatory potential of the same extracts was evaluated by their capacity to mitigate the pro-inflammatory stimulus induced in BV-2 microglia cells by interferon-gamma. ResultsT. catigua extract, a rich mixture of phenolic acids, catechins and flavonolignans, excels by its ability to decrease lipid peroxidation (EC50 = 227.18 ± 9.04 μg/mL), and to work as anti-glycation agent, and inhibitor of both tyrosinase and 5-lipoxigenase (IC50 = 358.84 ± 19.05 and 56.25 ± 14.53 μg/mL, respectively). However, only T. diffusa extract, mainly composed by luteolin derivatives, is able to lower NO production by BV-2 microglia cells stimulated with interferon-gamma, despite its lower activities in the other assays. ConclusionsOverall, this work highlights the value of medicinal plant extracts as sources of bioactive flavonoid-rich extracts with neuroactive effects. Furthermore, these results support their application as alternative strategies to develop functional foods and therapeutics to fight chronic neurodegenerative disorders.

Plant-Based Nutritional Supplementation Attenuates LPS-Induced Low-Grade Systemic Activation.

Plant-based nutritional supplementation has been shown to attenuate and reduce mortality in the processes of both acute and chronic disorders, including diabetes, obesity, cardiovascular disease, cancer, inflammatory diseases, and neurological and neurodegenerative disorders. Low-level systemic inflammation is an important contributor to these afflictions and diets enriched in phytochemicals can slow the progression. The goal of this study was to determine the impact of lipopolysaccharide (LPS)-induced inflammation on changes in glucose and insulin tolerance, performance enhancement, levels of urinary neopterin and concentrations of neurotransmitters in the striatum in mouse models. Both acute and chronic injections of LPS (2 mg/kg or 0.33 mg/kg/day, respectively) reduced glucose and insulin tolerance and elevated neopterin levels, which are indicative of systemic inflammatory responses. In addition, there were significant decreases in striatal neurotransmitter levels (dopamine and DOPAC), while serotonin (5-HT) levels were essentially unchanged. LPS resulted in impaired execution in the incremental loading test, which was reversed in mice on a supplemental plant-based diet, improving their immune function and maintaining skeletal muscle mitochondrial activity. In conclusion, plant-based nutritional supplementation attenuated the metabolic changes elicited by LPS injections, causing systemic inflammatory activity that contributed to both systemic and neurological alterations.

Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors

Ageing and Neurodegenerative Diseases is an open access multidisciplinary journal, focusing on innovative research advances in the cellular and molecular mechanisms underlying the ageing process and age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc., and therapeutic interventions in this field.

Oligodendrocyte precursor cell maturation: role of adenosine receptors.

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain and their degeneration leads to demyelinating diseases such as multiple sclerosis. Remyelination requires the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes but, in chronic neurodegenerative disorders, remyelination fails due to adverse environment. Therefore, a strategy to prompt oligodendrocyte progenitor cell differentiation towards myelinating oligodendrocytes is required. The neuromodulator adenosine, and its receptors (A1, A2A, A2B and A3 receptors: A1R, A2AR, A2BR and A3R), are crucial mediators in remyelination processes. It is known that A1Rs facilitate oligodendrocyte progenitor cell maturation and migration whereas the A3Rs initiates apoptosis in oligodendrocyte progenitor cells. Our group of research contributed to the field by demonstrating that A2AR and A2BR inhibit oligodendrocyte progenitor cell maturation by reducing voltage-dependent K+ currents necessary for cell differentiation. The present review summarizes the possible role of adenosine receptor ligands as potential therapeutic targets in demyelinating pathologies such as multiple sclerosis.

Neuroprotective effect of neferine, an alkaloid against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's disease mouse model

Background: Parkinson's disease (PD) is the second most chronic neurodegenerative disorders affecting the age-old peoples worldwide. Therefore, in the present study, we assessed the neuroprotective effect of neferine against the progressive Parkinson's induced mouse model. Mice were induced PD by treating them with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin selectively disrupts the dopaminergic neurons and then treated with neferine, a plant alkaloid. Materials and Methods: The neuroprotectant effect of neferine against MPTP-induced Parkinson's was assessed with behavioral analysis such as grid test and stride length measurement test, and the motor coordination was confirmed with rota rod test. Further, to assess the anti-inflammatory property of neferine, the levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β and IL-6 were estimated. Results: To confirm the neuroprotectant effect of neferine, the levels of dopamine and the protein expression of inducible nitric oxide synthase, cylcooxygenase-2, rate-limiting enzyme of dopamine synthesis tyrosine hydroxylase in the substantia nigra tissue of control and experimental mice were evaluated. Our overall results authentically prove that neferine acts an anti-inflammatory agent decreased the levels of pro-inflammatory cytokines and increased the dopamine levels in substantia nigra, thereby protecting the mice from MPTP-induced Parkinsonism. Conclusion: The behavioral analysis also confirmed neferine as a persuasive neuroprotectant with nil side effects and can be prescribed as a drug to treat Parkinson's with subject to further trials.

Response to Telemedicine Visits From Patients With Parkinsonism During the COVID-19 Pandemic on Postvisit Surveys.

Parkinson’s disease and parkinsonism are common chronic neurodegenerative disorders that tend to affect older adults and cause physical and sometimes cognitive limitations. Given that these limitations could impact successful telemedicine use, we aimed to investigate the experiences of patients with parkinsonism using telemedicine during the COVID-19 pandemic. A 19-item survey was emailed to patients with parkinsonism following telemedicine visits at a single US tertiary care parkinsonism specialty clinic. Seventy-four individuals responded, out of 270 invitations sent. Almost two-thirds (61.6%) of the respondents were comfortable with using technology in general, and almost all were very satisfied with their telemedicine experience. The most commonly reported benefits included cost and travel savings, ease of access to a specialist, and time savings. Issues with technology and previsit instructions were the most commonly identified challenges (28%). Urgent implementation, due to the pandemic, of telemedicine care for patients with parkinsonism was feasible and well received. The challenges most commonly reported by patients could be potentially alleviated by better education and support.

BACE1 Inhibitor, Neuroprotective, and Neuritogenic Activities of Melatonin Derivatives

Alzheimer’s disease (AD) is a common chronic neurodegenerative disorders. Melatonin (MLT) has been reported to be neuroprotective agent, and its modified structures exhibit potent antioxidant and anti-inflammation activities. Therefore, the activity of MLT and its derivatives against AD was investigated. Herein, the targeted enzymes, such as β-secretase (BACE1) and acetylcholinesterase (AChE), as well as the neuroprotective and neuritogenic effects on P19-derived neurons were evaluated. All the derivatives (1–5), including MLT, displayed potent inhibitory activity for BACE1, with inhibition values of more than 75% at 5 µM. A molecular docking study predicted that MLT, 5-MT, and 5 bound with BACE1 at catalytic amino acids Asp32 and the flap region, whereas 1–4 interacted with allosteric residue Thr232 and the flap region. The additional π-π interactions between 2, 3, and 5 with Tyr71 promoted ligand-enzyme binding. In addition, MLT, 1, 3, and 5 significantly protected neuron cells from oxidative stress by increasing the cell viability to 97.95, 74.29, 70.80, and 69.50% at 1 nM, respectively. Moreover, these derivatives significantly induced neurite outgrowth by increasing the neurite length and number. The derivatives 1, 3, and 5 should be thoroughly studied as potential AD treatment and neuroprotective agents.

Oligomeric α-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson's disease

Blood-based biomarkers are needed to be used as easy, reproducible, and non-invasive tools for the diagnosis and prognosis of chronic neurodegenerative disorders including Parkinson's Disease (PD). In PD, aggregated toxic forms of α-Synuclein (α-Syn) accumulate within neurons in the brain and cause neurodegeneration; α-Syn interaction with SNARE proteins also results in synaptic disfunction. We isolated neural derived extravesicles (NDEs) from peripheral blood of 32 PD patients and 40 healthy controls (HC) and measured the concentrations of oligomeric α-Syn and of the presinaptic SNARE complex proteins: STX-1A, VAMP-2 and SNAP-25. Oligomeric α-Syn was significantly augmented whereas STX-1A and VAMP-2 were significantly reduced in NDEs of PD patients compared to HC (p < 0.001 in all cases). ROC curve analyses confirmed the discriminatory ability of NDEs oligomeric α-Syn, STX-1A and VAMP-2 levels to distinguish between PD patients and HC. Oligomeric α-Syn NDEs concentration also positively correlated with disease duration and severity of PD. These results are promising and confirm that NDEs cargoes likely reflect core pathogenic intracellular processes in their originating brain cells and could serve as novel easily accessible bio-markers. Further studies are needed to confirm results and eventually for testing rehabilitation programs and drug treatments effects.

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis.

Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

Dysfunctional glia: contributors to neurodegenerative disorders.

Astrocytes are integral components of the central nervous system, where they are involved in numerous functions critical for neuronal development and functioning, including maintenance of blood-brain barrier, formation of synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These roles are markedly affected in the course of chronic neurodegenerative disorders, often before the onset of the disease. In this review, we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration. We focus on α-synucleinopathies and tauopathies as the most common neurodegenerative diseases. The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal, but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function. A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.

Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer\u2019s Disease mice

Leukotrienes (LTs) contribute to the neuropathology of chronic neurodegenerative disorders including Alzheimer’s Disease (AD), where they mediate neuroinflammation and neuronal cell-death. In consequence, blocking the action of Leukotrienes (LTs) ameliorates pathologies and improves cognitive function in animal models of neurodegeneration. Surprisingly, the source of Leukotrienes (LTs) in the brain is largely unknown. Here, we identified the Leukotriene (LT) synthesis rate-limiting enzyme 5-Lipoxygenase (5-Lox) primarily in neurons and to a lesser extent in a subpopulation of microglia in human Alzheimer´s Disease (AD) hippocampus brain sections and in brains of APP Swedish PS1 dE9 (APP-PS1) mice, a transgenic model for Alzheimer´s Disease (AD) pathology. The 5-Lipoxygenase (5-Lox) activating protein (FLAP), which anchors 5-Lipoxygenase (5-Lox) to the membrane and mediates the contact to the substrate arachidonic acid, was confined exclusively to microglia with the entire microglia population expressing 5-Lipoxygenase activating protein (FLAP). To define the contribution of microglia in the Leukotriene (LT) biosynthesis pathway, we ablated microglia using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in wildtype (WT) and APP-PS1 mice. Microglia ablation not only diminished the expression of FLAP and of the Leukotriene (LT) receptor Cysteinylleukotriene receptor 1 (CysLTR1), as expected based on their microglia cell type-specific expression, but also drastically reduced 5-Lipoxygenase (5-Lox) mRNA expression in the brain and its protein expression in neurons, in particular in wildtype (WT) mice. In conclusion i) microglia are key in Leukotriene (LT) biosynthesis, and ii) they regulate neuronal 5-Lipoxygenase (5-Lox) expression implying a yet unknown signaling mechanism between neurons and microglia.