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Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 36870

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Dr. Javier Garcia-Pardo

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Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autónoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Interests: bioactive compounds; cell signaling; drug delivery; drug discovery; enzymology; high-throughput screening; metalloproteases; molecular pharmacology; nanoparticles; neuropeptides; neurodegenerative diseases; parkinson's disease; protein-protein interaction inhibitors; protein engineering; protein structure; protease inhibitors; protein folding and aggregation; substrate specificity; X-ray crystallography
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Prof. Dr. Salvador Ventura

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1. Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, 08193 Bellaterra, Spain
2. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Spain
Interests: protein folding; protein aggregation; protein design; high-throughput screening; bioinformatics; amyloids; Parkinson; nanomaterials; phase separation; prions; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders are typically characterized by the progressive loss of specific populations of neurons in the brain. They can be classified according to a variety of primary clinical features and are associated with characteristic molecular abnormalities. The most common neurodegenerative disorders are amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies. Nearly all these disorders are associated with the accumulation of protein deposits and with alterations of normal proteostasis. Despite recent advances in the field, most of the molecular mechanisms involved in disease progression are not completely understood. However, since protein aggregation is a central event in neurological disorders, a variety of novel approaches are focused on developing novel pharmacologically active molecules targeting this process. In addition, our understanding of amyloid structures has been boosted by recent advances in the field of structural biology and cryo-EM, which have allowed the recent elucidation of a large number of high-resolution amyloid structures associated with neurodegeneration. Without doubt, such ground-breaking discoveries will facilitate the structure-based design of novel functional and specific protein aggregation inhibitors. Additionally, we focus on nanomaterials targeting neurodegenerative disorders as efficient drug delivery systems.

The focus of this Special Issue is on the development and identification of novel molecules and therapeutic approaches dedicated to treat neurodegenerative diseases. The topics include but are not limited to: the design and development of novel protein-aggregation inhibitors; drug delivery using nanotechnology; and the development and characterization of pharmacologically active compounds targeting proteostasis and neurodegeneration.

Dr. Javier Garcia-Pardo
Prof. Dr. Salvador Ventura
Guest Editors

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Keywords

neurodegenerative diseases
structure of amyloid fibrils
protein aggregation
Parkinson’s disease
amyloidoses
α-synucleinopathies
tauopathies
TDP-43 proteinopathies
cell signaling
drug discovery
drug delivery
nanotechnology
high-throughput screening
aggregation inhibitor
protease inhibitor
proteostasis

Related Special Issue

Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment, 2nd Edition in Pharmaceutics (2 articles)

Published Papers (12 papers)

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Research

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12 pages, 3107 KiB

Open AccessArticle

Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord

by Maria Izco, Martin Schleef, Marco Schmeer, Estefania Carlos, Guglielmo Verona and Lydia Alvarez-Erviti

Pharmaceutics 2023, 15(4), 1230; https://doi.org/10.3390/pharmaceutics15041230 - 13 Apr 2023

Cited by 3 | Viewed by 1647

Abstract

The development of effective disease-modifying therapies to halt Parkinson’s disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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16 pages, 8258 KiB

Open AccessArticle

Amelioration of Brain Damage after Treatment with the Methanolic Extract of Glycyrrhizae Radix et Rhizoma in Mice

by Myeongjin Choi, Chiyeon Lim, Boo-Kyun Lee and Suin Cho

Pharmaceutics 2022, 14(12), 2776; https://doi.org/10.3390/pharmaceutics14122776 - 12 Dec 2022

Cited by 3 | Viewed by 1439

Abstract

Glycyrrhizae Radix et Rhizoma (GR) is a traditional herbal medicine widely used in Asian countries. GR was the most frequently used medicine among stroke patients in Donguibogam, the most representative book in Korean medicine. In the present study, we investigated the neuroprotective effects of the GR methanolic extract (GRex) on an ischemic stroke mice model. Ischemic stroke was induced by a 90 min transient middle cerebral artery occlusion (MCAO), and GRex was administered to mice with oral gavage after reperfusion of MCA blood flow. The MCAO-induced edema and infarction volume was measured, and behavioral changes were evaluated by a novel object recognition test (NORT). Immunofluorescence stains and Western blotting identified underlying mechanisms of the protective effects of GRex. GRex post-treatment in mice with MCAO showed potent effects in reducing cerebral edema and infarction at 125 mg/kg but no effects when the dosage was much lower or higher than 125 mg/kg. GRex inhibited the decrease of spontaneous motor activity and novel object recognition functions. The neuroprotective effects of GRex on ischemic stroke were due to its regulation of inflammation-related neuronal cells, such as microglia and astrocytes. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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20 pages, 3284 KiB

Open AccessArticle

cGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function

by Sophie Wucherpfennig, Wadood Haq, Valerie Popp, Sandeep Kesh, Soumyaparna Das, Christian Melle, Andreas Rentsch, Frank Schwede, François Paquet-Durand and Vasilica Nache

Pharmaceutics 2022, 14(10), 2102; https://doi.org/10.3390/pharmaceutics14102102 - 01 Oct 2022

Cited by 4 | Viewed by 1551

Abstract

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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17 pages, 2476 KiB

Open AccessArticle

Direct Potential Modulation of Neurogenic Differentiation Markers by Granulocyte-Colony Stimulating Factor (G-CSF) in the Rodent Brain

by Judith Kozole, Rosmarie Heydn, Eva Wirkert, Sabrina Küspert, Ludwig Aigner, Tim-Henrik Bruun, Ulrich Bogdahn, Sebastian Peters and Siw Johannesen

Pharmaceutics 2022, 14(9), 1858; https://doi.org/10.3390/pharmaceutics14091858 - 02 Sep 2022

Viewed by 1457

Abstract

The hematopoietic granulocyte-colony stimulating growth factor (G-CSF, filgrastim) is an approved drug in hematology and oncology. Filgrastim’s potential in neurodegenerative disorders is gaining increasingly more attention, as preclinical and early clinical studies suggest it could be a promising treatment option. G-CSF has had a tremendous record as a safe drug for more than three decades; however, its effects upon the central nervous system (CNS) are still not fully understood. In contrast to conceptual long-term clinical application with lower dosing, our present pilot study intends to give a first insight into the molecular effects of a single subcutaneous (s.c.) high-dose G-CSF application upon different regions of the rodent brain. We analyzed mRNA—and in some instances—protein data of neurogenic and non-neurogenic differentiation markers in different regions of rat brains five days after G-CSF (1.3 mg/kg) or physiological saline. We found a continuous downregulation of several markers in most brain regions. Remarkably, cerebellum and hypothalamus showed an upregulation of different markers. In conclusion, our study reveals minor suppressive or stimulatory effects of a single exceptional high G-CSF dose upon neurogenic and non-neurogenic differentiation markers in relevant brain regions, excluding unregulated responses or unexpected patterns of marker expression. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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23 pages, 3802 KiB

Open AccessArticle

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

by Andrea Casiraghi, Francesca Longhena, Gaia Faustini, Giovanni Ribaudo, Lorenzo Suigo, Gisela Andrea Camacho-Hernandez, Federica Bono, Viviana Brembati, Amy Hauck Newman, Alessandra Gianoncelli, Valentina Straniero, Arianna Bellucci and Ermanno Valoti

Pharmaceutics 2022, 14(8), 1595; https://doi.org/10.3390/pharmaceutics14081595 - 30 Jul 2022

Cited by 5 | Viewed by 2290

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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Review

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46 pages, 2101 KiB

Open AccessReview

Photobiomodulation in Alzheimer’s Disease—A Complementary Method to State-of-the-Art Pharmaceutical Formulations and Nanomedicine?

by Laura Marinela Ailioaie, Constantin Ailioaie and Gerhard Litscher

Pharmaceutics 2023, 15(3), 916; https://doi.org/10.3390/pharmaceutics15030916 - 11 Mar 2023

Cited by 8 | Viewed by 5803

Abstract

Alzheimer’s disease (AD), as a neurodegenerative disorder, usually develops slowly but gradually worsens. It accounts for approximately 70% of dementia cases worldwide, and is recognized by WHO as a public health priority. Being a multifactorial disease, the origins of AD are not satisfactorily understood. Despite huge medical expenditures and attempts to discover new pharmaceuticals or nanomedicines in recent years, there is no cure for AD and not many successful treatments are available. The current review supports introspection on the latest scientific results from the specialized literature regarding the molecular and cellular mechanisms of brain photobiomodulation, as a complementary method with implications in AD. State-of-the-art pharmaceutical formulations, development of new nanoscale materials, bionanoformulations in current applications and perspectives in AD are highlighted. Another goal of this review was to discover and to speed transition to completely new paradigms for the multi-target management of AD, to facilitate brain remodeling through new therapeutic models and high-tech medical applications with light or lasers in the integrative nanomedicine of the future. In conclusion, new insights from this interdisciplinary approach, including the latest results from photobiomodulation (PBM) applied in human clinical trials, combined with the latest nanoscale drug delivery systems to easily overcome protective brain barriers, could open new avenues to rejuvenate our central nervous system, the most fascinating and complex organ. Picosecond transcranial laser stimulation could be successfully used to cross the blood-brain barrier together with the latest nanotechnologies, nanomedicines and drug delivery systems in AD therapy. Original, smart and targeted multifunctional solutions and new nanodrugs may soon be developed to treat AD. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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34 pages, 4121 KiB

Open AccessReview

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

by Samuel Peña-Díaz, Javier García-Pardo and Salvador Ventura

Pharmaceutics 2023, 15(3), 839; https://doi.org/10.3390/pharmaceutics15030839 - 03 Mar 2023

Cited by 10 | Viewed by 4441

Abstract

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by the accumulation of protein deposits in the dopaminergic neurons. These deposits are primarily composed of aggregated forms of α-Synuclein (α-Syn). Despite the extensive research on this disease, only symptomatic treatments are currently available. However, in recent years, several compounds, mainly of an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. These compounds, discovered by different approaches, are chemically diverse and exhibit a plethora of mechanisms of action. This work aims to provide a historical overview of the physiopathology and molecular aspects associated with Parkinson’s disease and the current trends in small compound development to target α-Syn aggregation. Although these molecules are still under development, they constitute an important step toward discovering effective anti-aggregational therapies for Parkinson’s disease. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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16 pages, 1805 KiB

Open AccessReview

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

by Menéndez-González Manuel, Bogdan-Ionel Tamba, Maxime Leclere, Mostafa Mabrouk, Thomas-Gabriel Schreiner, Romeo Ciobanu and Tomás-Zapico Cristina

Pharmaceutics 2023, 15(3), 768; https://doi.org/10.3390/pharmaceutics15030768 - 25 Feb 2023

Cited by 4 | Viewed by 1751

Abstract

Intrathecal pseudodelivery of drugs is a novel route to administer medications to treat neurodegenerative diseases based on the CSF-sink therapeutic strategy by means of implantable devices. While the development of this therapy is still in the preclinical stage, it offers promising advantages over traditional routes of drug delivery. In this paper, we describe the rationale of this system and provide a technical report on the mechanism of action, that relies on the use of nanoporous membranes enabling selective molecular permeability. On one side, the membranes do not permit the crossing of certain drugs; whereas, on the other side, they permit the crossing of target molecules present in the CSF. Target molecules, by binding drugs inside the system, are retained or cleaved and subsequently eliminated from the central nervous system. Finally, we provide a list of potential indications, the respective molecular targets, and the proposed therapeutic agents. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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26 pages, 12852 KiB

Open AccessReview

Plant-Derived Bioactive Compounds in the Management of Neurodegenerative Disorders: Challenges, Future Directions and Molecular Mechanisms Involved in Neuroprotection

by Shoaib Shoaib, Mohammad Azam Ansari, Adel Al Fatease, Awaji Y. Safhi, Umme Hani, Roshan Jahan, Mohammad N. Alomary, Mohd Nazam Ansari, Nabeel Ahmed, Shadma Wahab, Wasim Ahmad, Nabiha Yusuf and Najmul Islam

Pharmaceutics 2023, 15(3), 749; https://doi.org/10.3390/pharmaceutics15030749 - 23 Feb 2023

Cited by 10 | Viewed by 3047

Abstract

Neurodegenerative disorders encompass a wide range of pathological conditions caused by progressive damage to the neuronal cells and nervous-system connections, which primarily target neuronal dysfunction and result in problems with mobility, cognition, coordination, sensation, and strength. Molecular insights have revealed that stress-related biochemical alterations such as abnormal protein aggregation, extensive generation of reactive oxygen and nitrogen species, mitochondrial dysfunction, and neuroinflammation may lead to damage to neuronal cells. Currently, no neurodegenerative disease is curable, and the available standard therapies can only provide symptomatic treatment and delay the progression of the disease. Interestingly, plant-derived bioactive compounds have drawn considerable attention due to their well-established medicinal properties, including anti-apoptotic, antioxidant, anti-inflammatory, anticancer, and antimicrobial properties, as well as neuroprotective, hepatoprotective, cardioprotective, and other health benefits. Plant-derived bioactive compounds have received far more attention in recent decades than synthetic bioactive compounds in the treatment of many diseases, including neurodegeneration. By selecting suitable plant-derived bioactive compounds and/or plant formulations, we can fine tune the standard therapies because the therapeutic efficacy of the drugs is greatly enhanced by combinations. A plethora of in vitro and in vivo studies have demonstrated plant-derived bioactive compounds’ immense potential, as proven by their capacity to influence the expression and activity of numerous proteins implicated in oxidative stress, neuroinflammation, apoptosis, and aggregation. Thus, this review mostly focuses on the antioxidant, anti-inflammatory, anti-aggregation, anti-cholinesterase, and anti-apoptotic properties of several plant formulations and plant-derived bioactive compounds and their molecular mechanisms against neurodegenerative disorders. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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37 pages, 3035 KiB

Open AccessReview

Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology

by Man Amanat, Christina L. Nemeth, Amena Smith Fine, Doris G. Leung and Ali Fatemi

Pharmaceutics 2022, 14(11), 2389; https://doi.org/10.3390/pharmaceutics14112389 - 05 Nov 2022

Cited by 11 | Viewed by 7633

Abstract

Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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16 pages, 649 KiB

Open AccessReview

Targeting Emerging Pathogenic Mechanisms by Natural Molecules as Potential Therapeutics for Neurodegenerative Diseases

by Yan Dou and Dongju Zhao

Pharmaceutics 2022, 14(11), 2287; https://doi.org/10.3390/pharmaceutics14112287 - 25 Oct 2022

Cited by 2 | Viewed by 1441

Abstract

Natural molecules with favorable safety profile and broad pharmacological activities have shown great promise in the treatment of various neurodegenerative diseases (NDDs). Current studies applying natural molecules against NDDs mainly focus on well-recognized conventional pathogenesis, such as toxic protein aggregation, oxidative stress, and neuroinflammation. However, accumulating evidence reveals that some underlying pathogenic mechanisms are involved earlier and more deeply in the occurrence and development of NDDs, such as ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum stress, and gut dysbiosis. Therefore, determining whether natural molecules can play therapeutic roles in these emerging pathogenic mechanisms will help clarify the actual targets of natural molecules and their future clinical translation. Furthermore, how to overcome the inability of most poorly water-soluble natural molecules to cross the blood–brain barrier is also critical for effective NDD treatment. This review summarizes emerging pathogenic mechanisms targeted by natural molecules for NDD treatment, proposes nanocarrier-based drug delivery and intranasal administration to enhance the intracerebral bioavailability of natural molecules, and summarizes the current state of clinical research on natural product-based therapeutics. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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14 pages, 1648 KiB

Open AccessReview

Exploring the Involvement of the Amyloid Precursor Protein A673T Mutation against Amyloid Pathology and Alzheimer’s Disease in Relation to Therapeutic Editing Tools

by Gabriela Dumitrita Stanciu, Daniela Carmen Ababei, Razvan Nicolae Rusu, Veronica Bild and Bogdan-Ionel Tamba

Pharmaceutics 2022, 14(6), 1270; https://doi.org/10.3390/pharmaceutics14061270 - 15 Jun 2022

Cited by 3 | Viewed by 2220

Abstract

Alzheimer’s disease (AD) is biologically defined as a complex neurodegenerative condition with a multilayered nature that leads to a progressive decline in cognitive function and irreversible neuronal loss. It is one of the primary diseases among elderly individuals. With an increasing incidence and a high failure rate for pharmaceutical options that are merely symptom-targeting and supportive with many side effects, there is an urgent need for alternative strategies. Despite extensive knowledge on the molecular basis of AD, progress concerning effective disease-modifying therapies has proven to be a challenge. The ability of the CRISPR–Cas9 gene editing system to help identify target molecules or to generate new preclinical disease models could shed light on the pathogenesis of AD and provide promising therapeutic possibilities. Here, we sought to highlight the current understanding of the involvement of the A673T mutation in amyloid pathology, focusing on its roles in protective mechanisms against AD, in relation to the recent status of available therapeutic editing tools. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment)

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