Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both in vitro and in vivo, characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.

Neurodegenerative disorders (i.e., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and spinal cord injury) represent a great problem worldwide and are becoming prevalent because of the increasing average age of the population. Despite many studies having focused on their etiopathology, the exact cause of these diseases is still unknown and until now, there are only symptomatic treatments. Biomaterials have become important not only for the study of disease pathogenesis, but also for their application in regenerative medicine. The great advantages provided by biomaterials are their ability to mimic the environment of the extracellular matrix and to allow the growth of different types of cells. Biomaterials can be used as supporting material for cell proliferation to be transplanted and as vectors to deliver many active molecules for the treatments of neurodegenerative disorders. In this review, we aim to report the potentiality of biomaterials (i.e., hydrogels, nanoparticles, self-assembling peptides, nanofibers and carbon-based nanomaterials) by analyzing their use in the regeneration of neural and glial cells their role in axon outgrowth. Although further studies are needed for their use in humans, the promising results obtained by several groups leads us to suppose that biomaterials represent a potential therapeutic approach for the treatments of neurodegenerative disorders.

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis, Parkinson’s disease and Alzheimer’s disease. We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria’s life cycle: fusion, fission, production of reactive oxygen species and energy failure. Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes. Therefore, in order to get in depth insights into their health status in neurodegenerative diseases, we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes. Current techniques include Mitostress, Mitotracker, transmission electron microscopy, oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health. We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction. These include canonical drugs, natural compounds, supplements, lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy. In conclusion, because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases, it is critical to develop novel methods to measure the mitochondrial state, and novel therapeutic strategies aimed at improving their health.

In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture in vitro all types of patient-specific neural cells, facilitating not only the investigation of diseases’ etiopathology, but also the testing of new drugs and cell therapies, leading to the innovative concept of personalized medicine. Moreover, iPSCs can be differentiated and organized into 3D organoids, providing a tool which mimics the complexity of the brain’s architecture. Furthermore, recent developments in 3D bioprinting allowed the study of physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bio-plotter and biomaterials in which several types of cells, such as iPSCs or differentiated neurons, can be encapsulated in order to develop an innovative cellular model. IPSCs and 3D cell cultures technologies represent the first step towards the obtainment of a more reliable model, such as organoids, to facilitate neurodegenerative diseases’ investigation. The combination of iPSCs, 3D organoids and bioprinting will also allow the development of new therapeutic approaches. Indeed, on the one hand they will lead to the development of safer and patient-specific drugs testing but, also, they could be developed as cell-therapy for curing neurodegenerative diseases with a regenerative medicine approach.

In the field of regenerative medicine applied to neurodegenerative diseases, one of the most important challenges is the obtainment of innovative scaffolds aimed at improving the development of new frontiers in stem-cell therapy. In recent years, additive manufacturing techniques have gained more and more relevance proving the great potential of the fabrication of precision 3-D scaffolds. In this review, recent advances in additive manufacturing techniques are presented and discussed, with an overview on stimulus-triggered approaches, such as 3-D Printing and laser-based techniques, and deposition-based approaches. Innovative 3-D bioprinting techniques, which allow the production of cell/molecule-laden scaffolds, are becoming a promising frontier in disease modelling and therapy. In this context, the specific biomaterial, stiffness, precise geometrical patterns, and structural properties are to be considered of great relevance for their subsequent translational applications. Moreover, this work reports numerous recent advances in neural diseases modelling and specifically focuses on pre-clinical and clinical translation for scaffolding technology in multiple neurodegenerative diseases.

Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms.