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Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 September 2025) | Viewed by 19833

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Dr. Zhidong Zhou

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Guest Editor

National Neuroscience Institute of Singapore, Singapore City, Singapore
Interests: biomarkers; therapeutic targets and compounds for Parkinson's disease and other neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Alexandre Hiroaki Kihara

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Guest Editor

Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Santo André, Brazil
Interests: stem cells; sci; genome; CRISPR associated endonuclease Cas9; gene editing; electrocorticography; high frequency oscillation; seizures
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Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a group of heterogeneous disorders characterized with progressive neuron vulnerability and even neuron demise in the brain or peripheral nervous system, which are listed within the leading causes for human death. Among various neurodegenerative conditions, Alzheimer's disease and Parkinson's disease (PD) are the most common neurodegenerative disorders. With the aging of our population, the prevalence of neurodegenerative diseases increases significantly, posing serious healthy and economic challenges all around the world. Although oxidative stress, protein aggregation, mitochondria impairment, and neuroinflammation are relevant to neurodegeneration, the disease pathogenesis are not fully understood and no therapy available for these degenerative disorders. Recently, cell therapies using human cell derived dopamine neurons to replace lost neurons in PD patient brains show promise and the first human clinical trial of transplantation of induced pluripotent stem cells derived human dopamine progenitors is under investigation in the Center for iPS Cell Research and Application (CiRA), Kyoto University, which brings hopes to patients with PD and other degenerative diseases.

The aim of this Special Issue is to discuss the disease pathogenesis and new therapeutic agents or therapeutic strategies to protect or alleviate neurodegeneration in human neurodegenerative disorders.

Dr. Zhidong Zhou
Dr. Alexandre Hiroaki Kihara
Guest Editors

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Keywords

neurodegeneration
neurodegenerative diseases
protein aggregation
pathogenesis
therapy
mitochondria
neuroinflammation
oxidative stress
cell therapy
clinical trial

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Published Papers (8 papers)

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Research

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22 pages, 3089 KB

Open AccessArticle

Cladribine Preserves Normal Central Nervous System Cellular Activity and Promotes Neuroprotection to Oxidative Stress Damage

by Herena Eixarch, Laura Calvo-Barreiro, Nicolás Fissolo, Ursula Boschert, Arnau Hervera, Manuel Comabella, Xavier Montalban and Carmen Espejo

Int. J. Mol. Sci. 2025, 26(23), 11311; https://doi.org/10.3390/ijms262311311 - 22 Nov 2025

Viewed by 372

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease that causes disability in patients. Cladribine is an oral treatment that is used in relapsing–remitting and active secondary progressive MS. T and B lymphocytes are especially sensitive to cladribine, which are transiently depleted upon short treatment courses. However, cladribine crosses the blood–brain barrier (BBB), supporting the hypothesis that cladribine may affect central nervous system (CNS)-resident cells. In this study, we used human primary cells and human cell lines to test the effect of cladribine, at therapeutic concentrations, on cells of the CNS. In these conditions, cladribine did not affect survival, proliferation and the capacity of producing cytokines of human microglial cells (HMC3 cell line) or primary human astrocytes but enhanced the production of oxygen reactive species in both cell types. The initial differentiation of primary human neuronal progenitor cells was impaired when continuously exposed to the maximum therapeutic concentration of cladribine, but not when lower concentrations were used. However, cladribine protected differentiated SH-SY5Y human neuroblastoma cell line from oxidative stress-related cell death. In conclusion, using different in vitro cell models, we demonstrate that cladribine maintains the normal function of CNS glia and protects neuronal cells from oxidative stress damage. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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24 pages, 2722 KB

Open AccessArticle

Perinatal Ethanol Exposure Induces Astrogliosis and Decreases GRP55/PEA-Mediated Neuroprotection in Hippocampal Astrocytes of the 3×Tg Alzheimer’s Animal Model

by Miguel Rodríguez-Pozo, Beatriz Pacheco-Sánchez, Meriem Ben Rabaa, Marialuisa de Ceglia, Sonia Melgar-Locatelli, Ignacio Santos, Fernando Rodríguez de Fonseca, Juan Suárez and Patricia Rivera

Int. J. Mol. Sci. 2025, 26(22), 11154; https://doi.org/10.3390/ijms262211154 - 18 Nov 2025

Viewed by 482

Abstract

Prenatal ethanol exposure (PEE) alters fetal brain development, potentially increasing the risk of neurodegenerative diseases such as Alzheimer’s disease (AD) later in life. Although glial activation is implicated in AD pathology via cannabinoid and neuroinflammatory signaling, its potential response to PEE in the developing brain and its contribution to AD pathogenesis remain unknown. Using 3×Tg-AD offspring of both sexes born to mothers with PEE, we analyzed astrogliosis, inflammatory markers, and key components of cannabinoid and Ca²⁺ signaling in primary cultures of hippocampal astrocytes, elements whose dysfunction contributes to neurodegeneration. Our results indicated that PEE increased astrogliosis/inflammatory response (significant elevation of Gfap and Tnfα expression) in hippocampal astrocytes at birth. This neuroinflammation was significantly associated with lower expression of cannabinoid receptors (Cnr1 and Gpr55), and decreased concentrations of the anti-inflammatory lipid PEA in the culture medium, probably due to a deregulated endocannabinoid enzymatic machinery (NAPE-PLD/FAAH ratio). This research provides insights into GRP55/PEA-mediated signaling as a potential hippocampal astrocytic mechanism influenced by maternal ethanol exposure, which may contribute to neurobiological changes associated with increased vulnerability to AD-related pathology. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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21 pages, 2070 KB

Open AccessArticle

Contribution of Cerebellar Glutamatergic and GABAergic Systems in Premotor and Early Stages of Parkinson’s Disease

by Clelia Pellicano, Daniela Vecchio, Federico Giove, Lucia Macchiusi, Marco Clemenzi, Claudia Marzi, Mariana Fernandes, Flavia Cirillo, Silvia Maio, Claudio Liguori, Fabrizio Piras and Federica Piras

Int. J. Mol. Sci. 2025, 26(21), 10754; https://doi.org/10.3390/ijms262110754 - 5 Nov 2025

Viewed by 450

Abstract

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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11 pages, 1321 KB

Open AccessArticle

Possible Impact of Peripheral Inflammatory Factors and Interleukin-1β (IL-1β) on Cognitive Functioning in Progressive Supranuclear Palsy–Richardson Syndrome (PSP-RS) and Progressive Supranuclear Palsy–Predominant Parkinsonism (PSP-P)

by Patryk Chunowski, Dagmara Otto-Ślusarczyk, Karolina Duszyńska-Wąs, Agnieszka Drzewińska, Andrzej Załęski, Natalia Madetko-Alster, Alicja Wiercińska-Drapało, Marta Struga and Piotr Alster

Int. J. Mol. Sci. 2024, 25(23), 13211; https://doi.org/10.3390/ijms252313211 - 9 Dec 2024

Cited by 3 | Viewed by 1466

Abstract

Progressive supranuclear palsy (PSP) is a tauopathic atypical parkinsonian syndrome. Recent studies suggest that inflammation may play a role in PSP pathogenesis, highlighting markers like the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and cytokines such as IL-1β and IL-6. This study aimed to assess the relationship between peripheral inflammatory markers and psychological abnormalities in PSP-RS and PSP-P patients. The study included 24 participants: 12 with PSP-RS, 12 with PSP-P, and 12 controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA); however, the executive functions were evaluated using the Frontal Assessment Battery (FAB), while inflammatory markers such as IL-1β, IL6, NLR, and PLR were measured. The parameter correlation was executed using Spearman’s correlation (rs). The analysis revealed significant negative correlations between NLR and MoCA (rs = −0.48), as well as between PLR and MoCA (rs = −0.60). The negative correlation between IL-1β and MoCA was statistically significant but relatively weak. This study highlights the relevance of inflammatory markers such as NLR and PLR in reflecting cognitive decline in PSP patients, with IL-1β potentially playing a protective role in cognitive function. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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22 pages, 6840 KB

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Noradrenaline Protects Human Microglial Cells (HMC3) Against Apoptosis and DNA Damage Induced by LPS and Aβ_1-42 Aggregates In Vitro

by Julia Barczuk, Grzegorz Galita, Natalia Siwecka, Michał Golberg, Kamil Saramowicz, Zuzanna Granek, Wojciech Wiese, Ireneusz Majsterek and Wioletta Rozpędek-Kamińska

Int. J. Mol. Sci. 2024, 25(21), 11399; https://doi.org/10.3390/ijms252111399 - 23 Oct 2024

Cited by 1 | Viewed by 3446

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) plaques and neuroinflammation. This study investigates the protective effects of noradrenaline (NA) on human microglial cells exposed to lipopolysaccharides (LPS) and Aβ aggregates—major contributors to inflammation and cellular damage in AD. The reduced Aβ aggregation in the HMC3 human microglial cells co-treated with Aβ and NA was confirmed by thioflavin T (ThT) assay, fluorescent ThT staining, and immunocytochemistry (ICC). The significantly increased viability of HMC3 cells after 48 h of incubation with NA at 50 µM, 25 µM, and 10 µM, exposed to IC50 LPS and IC50 Aβ, was confirmed by XTT and LDH assays. Moreover, we found that NA treatment at 25 μM and 50 μM concentrations in HMC3 cells exposed to IC50 LPS or IC50 Aβ results in an increased proliferation of HMC3 cells, their return to normal morphology, decreased levels of DNA damage, reduced caspase-3 activity, decreased expression of pro-apoptotic DDIT3 and BAX, and increased expression of anti-apoptotic BCL-2 genes and proteins, leading to enhanced cell survival, when compared to that of the HMC3 cells treated only with IC50 LPS or IC50 Aβ. Furthermore, we showed that NA induces the degradation of both extracellular and intracellular Aβ deposits and downregulates hypoxia-inducible factor 1α (HIF-1α), which is linked to impaired Aβ clearance and AD progression. These findings indicate that NA holds promise as a therapeutic target to address microglial dysfunction and potentially slow the progression of AD. Its neuroprotective effects, particularly in reducing inflammation and regulating microglial activity, warrant further investigation into its broader role in mitigating neuroinflammation and preserving microglial function in AD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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25 pages, 2185 KB

Open AccessReview

Therapeutic Potential for Cannabidiol on Alzheimer’s Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis

by Shuo Wu, Tracia Rajiah and Afia B. Ali

Int. J. Mol. Sci. 2025, 26(24), 11963; https://doi.org/10.3390/ijms262411963 - 11 Dec 2025

Abstract

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder characterized by chronic neuroinflammation; current interventions primarily offer symptomatic relief. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits multi-target therapeutic potential due to its established anti-inflammatory and neuroprotective properties. While growing interest exists, the evidence regarding CBD’s effects on AD-related neuroinflammation has not been robustly consolidated in a quantitative meta-analysis. Therefore, this article reviews the current literature around CBD related to its potential in alleviating neuroinflammation, followed by a meta-analysis of preclinical and clinical studies using random-effects modeling to assess CBD efficacy on neuroinflammation and clinical outcomes in AD. In preclinical AD models, the meta-analysis demonstrated that CBD significantly and consistently reduced key markers of neuroinflammation and reactive gliosis, specifically glial fibrillary acidic protein (GFAP) (p < 0.0001), Interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). Effects on other markers, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), were non-significant and heterogeneous. Clinical evidence, though limited by small sample size and heterogeneity, showed a borderline significant benefit favoring CBD for overall behavioral symptoms (p = 0.05), agitation, and caregiver distress. Adverse events were typically mild. We conclude that CBD demonstrates biologically consistent anti-inflammatory efficacy in preclinical AD models. While current clinical data remains insufficient to substantiate efficacy, they suggest promising signals for behavioral control. Determining CBD’s full therapeutic potential in AD necessitates future rigorous, mechanism-driven trials with standardized preparations and biomarker-anchored endpoints. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

26 pages, 1649 KB

Open AccessReview

Train and Reprogram Your Brain: Effects of Physical Exercise at Different Stages of Life on Brain Functions Saved in Epigenetic Modifications

by Magdalena Kukla-Bartoszek and Katarzyna Głombik

Int. J. Mol. Sci. 2024, 25(22), 12043; https://doi.org/10.3390/ijms252212043 - 9 Nov 2024

Cited by 4 | Viewed by 8941

Abstract

Multiple studies have demonstrated the significant effects of physical exercise on brain plasticity, the enhancement of memory and cognition, and mood improvement. Although the beneficial impact of exercise on brain functions and mental health is well established, the exact mechanisms underlying this phenomenon are currently under thorough investigation. Several hypotheses have emerged suggesting various possible mechanisms, including the effects of hormones, neurotrophins, neurotransmitters, and more recently also other compounds such as lactate or irisin, which are released under the exercise circumstances and act both locally or/and on distant tissues, triggering systemic body reactions. Nevertheless, none of these actually explain the long-lasting effect of exercise, which can persist for years or even be passed on to subsequent generations. It is believed that these long-lasting effects are mediated through epigenetic modifications, influencing the expression of particular genes and the translation and modification of specific proteins. This review explores the impact of regular physical exercise on brain function and brain plasticity and the associated occurrence of epigenetic modifications. It examines how these changes contribute to the prevention and treatment of neuropsychiatric and neurological disorders, as well as their influence on the natural aging process and mental health. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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10 pages, 274 KB

Open AccessCommentary

The α-Synuclein Seeding Amplification Assay for Parkinson’s Disease

by Ling-Xiao Yi, Eng King Tan and Zhi Dong Zhou

Int. J. Mol. Sci. 2025, 26(1), 389; https://doi.org/10.3390/ijms26010389 - 4 Jan 2025

Cited by 7 | Viewed by 3654

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Currently, PD is incurable, and the diagnosis of PD mainly relies on clinical manifestations. The central pathological event in PD is the abnormal aggregation and deposition of misfolded α-synuclein (α-Syn) protein aggregates in the Lewy body (LB) in affected brain areas. Behaving as a prion-like seeding, the misfolded α-syn protein can induce and facilitate the aggregation of native unfolded α-Syn protein to aggravate α-Syn protein aggregation, leading to PD progression. Recently, in a blood-based α-Syn seeding amplification assay (SAA), Kluge et al. identified pathological α-Syn seeding activity in PD patients with Parkin (PRKN) gene variants. Additionally, pathological α-syn seeding activity was also identified in sporadic PD and PD patients with Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) gene variants. Principally, the α-Syn SAA can be used to detect pathological α-Syn seeding activity, which will significantly enhance PD diagnosis, progression monitoring, prognosis prediction, and anti-PD therapy. The significance and future strategies of α-Syn SAA protocol are highlighted and proposed, whereas challenges and limitations of the assay are discussed. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 3rd Edition)

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