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.     

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.     

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection

The function of the brain-derived neurotrophic factor (BDNF) via activation through its high-affinity receptor Tropomyosin receptor kinase B (TrkB) has a pivotal role in cell differentiation, cell survival, synaptic plasticity, and both embryonic and adult neurogenesis in central nervous system neurons. A number of studies have demonstrated the possible involvement of altered expression and action of the BDNF/TrkB signaling in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). In this review, we introduce an essential role of the BDNF and its downstream signaling in neural function. We also review the current evidence on the deregulated the BDNF signaling in the pathophysiology of AD at gene, mRNA, and protein levels. Further, we discuss a potential usefulness of small compounds, including flavonoids, which can stimulate BDNF-related signaling as a BDNF-targeting therapy.     

Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action.     

The Role of Neurotrophin Signaling in Age-Related Cognitive Decline and Cognitive Diseases

Neurotrophins are a family of secreted proteins expressed in the peripheral nervous system and the central nervous system that support neuronal survival, synaptic plasticity, and neurogenesis. Brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB are highly expressed in the cortical and hippocampal areas and play an essential role in learning and memory. The decline of cognitive function with aging is a major risk factor for cognitive diseases such as Alzheimer’s disease. Therefore, an alteration of BDNF/TrkB signaling with aging and/or pathological conditions has been indicated as a potential mechanism of cognitive decline. In this review, we summarize the cellular function of neurotrophin signaling and review the current evidence indicating a pathological role of neurotrophin signaling, especially of BDNF/TrkB signaling, in the cognitive decline in aging and age-related cognitive diseases. We also review the therapeutic approach for cognitive decline by the upregulation of the endogenous BDNF/TrkB-system.     

Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease,Lithium, and Autophagy

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug’s neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium’s neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug’s inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium’s neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer’s disease (AD) and in patients, discussing the rationale for the drug’s use in the treatment of AD.     

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.     

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.     

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

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

Alzheimer’s Disease: From Immune Homeostasis to Neuroinflammatory Condition

Alzheimer’s Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer’s Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aβ plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells’ activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer’s Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition.     

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.     

The Role of Epigenetics in Neuroinflammatory-Driven Diseases

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

Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease

α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause familial forms of PD. Moreover, the ectopic expression of αSyn has been demonstrated to mimic several key aspects of PD in experimental model systems. Among the various model systems, Drosophila melanogaster has several advantages for modeling human neurodegenerative diseases. Drosophila has a well-defined nervous system, and numerous tools have been established for its genetic analyses. The rapid generation cycle and short lifespan of Drosophila renders them suitable for high-throughput analyses. PD model flies expressing αSyn have contributed to our understanding of the roles of various disease-associated factors, including genetic and nongenetic factors, in the pathogenesis of PD. In this review, we summarize the molecular pathomechanisms revealed to date using αSyn-expressing Drosophila models of PD, and discuss the possibilities of using these models to demonstrate the biological significance of disease-associated factors.     

Wharton’s Jelly-Derived Mesenchymal Stem Cells: Phenotypic Characterization and Optimizing Their Therapeutic Potential for Clinical Applications

Wharton’s jelly (WJ) is a gelatinous tissue within the umbilical cord that contains myofibroblast-like stromal cells. A unique cell population of WJ that has been suggested as displaying the stemness phenotype is the mesenchymal stromal cells (MSCs). Because MSCs’ stemness and immune properties appear to be more robustly expressed and functional which are more comparable with fetal than adult-derived MSCs, MSCs harvested from the “young” WJ are considered much more proliferative, immunosuppressive, and even therapeutically active stem cells than those isolated from older, adult tissue sources such as the bone marrow or adipose. The present review discusses the phenotypic characteristics, therapeutic applications, and optimization of experimental protocols for WJ-derived stem cells. MSCs derived from WJ display promising transplantable features, including ease of sourcing, in vitro expandability, differentiation abilities, immune-evasion and immune-regulation capacities. Accumulating evidence demonstrates that WJ-derived stem cells possess many potential advantages as transplantable cells for treatment of various diseases (e.g., cancer, chronic liver disease, cardiovascular diseases, nerve, cartilage and tendon injury). Additional studies are warranted to translate the use of WJ-derived stem cells for clinical applications.     

PARK7/DJ-1 as a Therapeutic Target in Gut-Brain Axis Diseases

It is increasingly known that Parkinson’s (PD) and Alzheimer’s (AD) diseases occur more frequently in patients with inflammatory gastrointestinal diseases including inflammatory bowel (IBD) or celiac disease, indicating a pathological link between them. Although epidemiological observations suggest the existence of the gut-brain axis (GBA) involving systemic inflammatory and neural pathways, little is known about the exact molecular mechanisms. Parkinson’s disease 7 (PARK7/DJ-1) is a multifunctional protein whose protective role has been widely demonstrated in neurodegenerative diseases, including PD, AD, or ischemic stroke. Recent studies also revealed the importance of PARK7/DJ-1 in the maintenance of the gut microbiome and also in the regulation of intestinal inflammation. All these findings suggest that PARK7/DJ-1 may be a link and also a potential therapeutic target in gut and brain diseases. In this review, therefore, we discuss our current knowledge about PARK7/DJ-1 in the context of GBA diseases.     

Neuroinflammation and Autophagy in Parkinson’s Disease—Novel Perspectives

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the accumulation of α-Synuclein aggregates and the degeneration of dopaminergic neurons in substantia nigra in the midbrain. Although the exact mechanisms of neuronal degeneration in PD remain largely elusive, various pathogenic factors, such as α-Synuclein cytotoxicity, mitochondrial dysfunction, oxidative stress, and pro-inflammatory factors, may significantly impair normal neuronal function and promote apoptosis. In this context, neuroinflammation and autophagy have emerged as crucial processes in PD that contribute to neuronal loss and disease development. They are regulated in a complex interconnected manner involving most of the known PD-associated genes. This review summarizes evidence of the implication of neuroinflammation and autophagy in PD and delineates the role of inflammatory factors and autophagy-related proteins in this complex condition. It also illustrates the particular significance of plasma and serum immune markers in PD and their potential to provide a personalized approach to diagnosis and treatment.     

The Intersection of Human and Veterinary Medicine—A Possible Direction towards the Improvement of Cell Therapy Protocols in the Treatment of Perianal Fistulas

The effective treatment of perianal fistulizing Crohn’s disease is still a challenge. Local administration of mesenchymal stromal cells (MSCs) is becoming a part of accepted treatment options. However, as a fledgling technique, it still can be optimized. A new trend in translational research, which is in line with “One Health” approach, bases on exploiting parallels between naturally occurring diseases affecting humans and companion animals. Canine anal furunculosis (AF) has been indicated as condition analogous to human perianal Crohn’s disease (pCD). This narrative review provides the first comprehensive comparative analysis of these two diseases based on the published data. The paper also outlines the molecular mechanisms of action of MSCs which are likely to have a role in modulating the perianal fistula niche in humans, and refers them to the current knowledge on the immunomodulatory properties of canine MSCs. Generally, the pathogenesis of both diseases shares main determinants such as the presence of genetic predispositions, dysregulation of immune response and the relation to intestine microbiota. However, we also identified many aspects which should be further specified, such as determining the frequency of true fistulas formation in AF patients, elucidating the role of TNF and Th17 pathway in the pathogenesis of AF, or clarifying the role of epithelial-to-mesenchymal transition phenomenon in the formation of canine fistulae. Nevertheless, the available data support the hypothesis that the results from testing cell therapies in dogs with anal furunculosis have a significant translational value in optimizing MSC transplants procedures in pCD patients.