Erythropoietin: New Directions for the Nervous System

New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer’s disease, Parkinson’s disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.     

Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases

Neurotrophic factors (NTFs) are essential for cell growth, survival, synaptic plasticity, and maintenance of specific neuronal population in the central nervous system. Multiple studies have demonstrated that alterations in the levels and activities of NTFs are related to the pathology and symptoms of neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease. Hence, the key molecule that can regulate the expression of NTFs is an important target for gene therapy coupling adeno-associated virus vector (AAV) gene. We have previously reported that the Ras homolog protein enriched in brain (Rheb)–mammalian target of rapamycin complex 1 (mTORC1) axis plays a vital role in preventing neuronal death in the brain of AD and PD patients. AAV transduction using a constitutively active form of Rheb exerts a neuroprotective effect through the upregulation of NTFs, thereby promoting the neurotrophic interaction between astrocytes and neurons in AD conditions. These findings suggest the role of Rheb as an important regulator of the regulatory system of NTFs to treat neurodegenerative diseases. In this review, we present an overview of the role of Rheb in neurodegenerative diseases and summarize the therapeutic potential of AAV serotype 1 (AAV1)-Rheb(S16H) transduction in the treatment of neurodegenerative disorders, focusing on diseases, such as AD and PD.     

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

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

Histone Methylation Regulation in Neurodegenerative Disorders

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

Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders

The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.     

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

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

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia,Alzheimer’s,and Parkinson’s Diseases

Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain.     

Complement System in Alzheimer’s Disease

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

Use of Genetically Modified Mesenchymal Stem Cells to Treat Neurodegenerative Diseases

The transplantation of mesenchymal stem cells (MSCs) for treating neurodegenerative disorders has received growing attention recently because these cells are readily available, easily expanded in culture, and when transplanted, survive for relatively long periods of time. Given that such transplants have been shown to be safe in a variety of applications, in addition to recent findings that MSCs have useful immunomodulatory and chemotactic properties, the use of these cells as vehicles for delivering or producing beneficial proteins for therapeutic purposes has been the focus of several labs. In our lab, the use of genetic modified MSCs to release neurotrophic factors for the treatment of neurodegenerative diseases is of particular interest. Specifically, glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) have been recognized as therapeutic trophic factors for Parkinson’s, Alzheimer’s and Huntington’s diseases, respectively. The aim of this literature review is to provide insights into: (1) the inherent properties of MSCs as a platform for neurotrophic factor delivery; (2) the molecular tools available for genetic manipulation of MSCs; (3) the rationale for utilizing various neurotrophic factors for particular neurodegenerative diseases; and (4) the clinical challenges of utilizing genetically modified MSCs.     

Adiponectin Role in Neurodegenerative Diseases: Focus on Nutrition Review

Adiponectin is an adipokine produced by adipose tissue. It has numerous beneficial effects. In particular, it improves metabolic effects and glucose homeostasis, lipid profile, and is involved in the regulation of cytokine profile and immune cell production, having anti-inflammatory and immune-regulatory effects. Adiponectin’s role is already known in immune diseases and also in neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are a set of diseases of the central nervous system, characterized by a chronic and selective process of neuron cell death, which occurs mainly in relation to oxidative stress and neuroinflammation. Lifestyle is able to influence the development of these diseases. In particular, unhealthy nutrition on gut microbiota, influences its composition and predisposition to develop many diseases such as neurodegenerative diseases, given the importance of the “gut-brain” axis. There is a strong interplay between Adiponectin, gut microbiota, and brain-gut axis. For these reasons, a healthy diet composed of healthy nutrients such as probiotics, prebiotics, polyphenols, can prevent many metabolic and inflammatory diseases such as neurodegenerative diseases and obesity. The special Adiponectin role should be taken into account also, in order to be able to use this component as a therapeutic molecule.     

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.     

Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation

Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.     

Peripheral Glycolysis in Neurodegenerative Diseases

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.     

Highlighting Immune System and Stress in Major Depressive Disorder,Parkinson’s,and Alzheimer’s Diseases,with a Connection with Serotonin

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.     

Parkinson’s Disease: A Complex Interplay of Mitochondrial DNA Alterations and Oxidative Stress

Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD etiology, in particular, of the Base Excision Repair (BER) system. In addition, recent findings, related to PD progression, indicate that oxidative stress pathways involving c-Abl and GST could also be implicated in this pathology. This review focuses on recently described networks most likely involved in an integrated manner in the course of PD.     

Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.     

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

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