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Neurodegenerative Disease: From Molecular Basis to Therapy, 4th 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: 20 March 2026 | Viewed by 7839

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Dr. Claudia Ricci

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Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
Interests: molecular biology; neurogenetics; motor neuron diseases; amyotrophic lateral sclerosis; gene variants; gene regulation
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Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a heterogeneous, largely age-dependent group of disorders that affect the central nervous system and ultimately lead to neurodegeneration. The prevalence of these diseases is increasing, partly due to the aging population, with a consequent growing economic burden on healthcare systems. Current treatments are mostly symptomatic, do not address the underlying cause of disease, and have little or no effect on disease progression.

Recent advancements in neurobiology and neurogenetics have provided valuable insights into the pathogenesis of neurodegenerative diseases. This has paved the way for the development of molecularly targeted therapies that can pause or slow the fundamental pathological processes that cause neuronal damage and consequent cognitive and motor dysfunctions. In some cases, neurodegenerative diseases are caused by genetic variants and/or cellular pathway dysregulation. Some mechanisms common to several neurodegenerative conditions have been identified, such as the presence of misfolded protein aggregates, the abnormal accumulation of proteins, RNA toxicity, and translational products from the expansion of repeats within genes. As advances are made in understanding critical aspects of the underlying molecular pathophysiology, therapeutic strategies continue to evolve. Among these, gene therapy is attracting great interest because of its ability to deliver functional genetic material to cells to correct defective genes.

This Special Issue aims to provide an updated overview of the advancements in the research on neurodegenerative diseases, from the understanding of the molecular bases to the development of new therapies. Contributions related to, but not limited to, Alzheimer's disease and other types of dementia, Parkinson's disease, and motor neuron diseases are welcome, including original research articles as well as full and short reviews.

Dr. Claudia Ricci
Guest Editor

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Keywords

neurodegenerative diseases
molecular biology
neurogenetics
pathogenesis
therapy
personalized medicine

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Published Papers (8 papers)

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Research

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20 pages, 1556 KB

Open AccessArticle

Oral and Periodontal Health Status, Peripheral Immune Dysregulation, and Cognitive Impairment in Alzheimer’s Disease: A Clinical and Immunological Study

by Michał Ochnik, Jacek Zborowski, Jerzy Leszek, Adrianna Senczyszyn, Breno Satler Diniz, Aleksandra Sender-Janeczek, Egbert Piasecki and Marta Sochocka

Int. J. Mol. Sci. 2025, 26(23), 11752; https://doi.org/10.3390/ijms262311752 - 4 Dec 2025

Viewed by 308

Abstract

Periodontal disease (PeD), a chronic oral infectious-inflammatory condition, has been linked to systemic inflammatory processes, which may contribute to the onset or progression of various systemic disorders including Alzheimer’s disease (AD). We hypothesized that worsening oral and periodontal health, leading to the development of PeD, is associated with cognitive impairment and AD progression as well as peripheral immune system dysregulation. This study included 68 participants: 36 with AD and 32 cognitively healthy, age-matched controls (HCs). Periodontal assessment was performed for diagnosis of PeD (gingivitis or periodontitis). Correlations between oral and periodontal health status, cognitive impairment, and AD severity were evaluated. Peripheral immunity markers were investigated. Peripheral blood leukocytes (PBLs) were stimulated ex vivo with LPS from Porphyromonas gingivalis (LPS-PG) to assess cytokine IFN-γ, TNF-α, IL-1β, IL-6, IL-10, and IL-15 production. The average levels of peripheral immunity markers were significantly lower in AD compared to HCs. AD severity was associated with poorer oral hygiene and increased periodontal tissue inflammation. PBLs from AD patients exhibited a baseline impairment in immune responsiveness reflected in decreased spontaneous TNF-α, IL-1β, IL-6, and IL-10 production. Nevertheless, stronger activation in response to LPS-PG was observed. Poorer oral health status in AD was associated with reduced levels of IL-10 and IL-6. Poor oral and periodontal health may contribute to cognitive impairment and AD progression. Even mild inflammation in periodontal tissue or gingivitis may already influence peripheral immune cell conditions, which in turn might be related to negative consequences for the brain and mental health. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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22 pages, 3108 KB

Open AccessArticle

Amyloid β Peptide Modifies Membrane Architecture and Surface Electrostatic Properties of Human Red Blood Cells

by Galya Staneva, Vesela Yordanova, Avgustina Danailova, Ana-Maria Marinovska, András Dér and Stefka G. Taneva

Int. J. Mol. Sci. 2025, 26(23), 11361; https://doi.org/10.3390/ijms262311361 - 24 Nov 2025

Viewed by 417

Abstract

Abnormal accumulation of amyloid-beta (Aβ) peptides in the brain is a hallmark of Alzheimer’s disease (AD). Importantly, the peripheral blood cells are also exposed to the effects of pathological peptides that accumulate in AD. Herein, the interaction of Aβ42 oligomers (Aβ42) with human red blood cells (RBCs) and erythrocyte ghosts as in vitro models for AD is studied combining fluorescence spectroscopy, fluorescence microscopy, and electrokinetics. The binding of Aβ42 to RBCs was evidenced by the use of a fluorescent-labeled peptide. The membrane lipid order increased with the increase in both the Aβ42 concentration and the incubation time, creating a lipid–protein microenvironment characterized by higher molecular order and reduced heterogeneity in RBC membranes compared to control conditions. Notably, the increase in lipid order was less pronounced in erythrocyte ghosts than in intact RBCs. Furthermore, the ζ-potential measurements revealed Aβ42 induced alteration of the surface potential of RBCs in a concentration- and time-dependent manner, with freshly isolated RBCs exhibiting a highly negative potential that became increasingly negative at higher Aβ42 concentrations. These findings suggest that Aβ42 not only impacts neuronal function but also significantly alters the physical properties of RBCs that might compromise their function, potentially contributing to the systemic effects observed in AD. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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17 pages, 6187 KB

Open AccessArticle

Generation of Induced Pluripotent Stem Cells and Neuroepithelial Stem Cells from a Family with the Pathogenic Variant p.Q337X in Progranulin

by Katarzyna Gaweda-Walerych, Adam Figarski, Sylwia Gawlik-Zawiślak, Marta Woźniak, Anna Chołoniewska, Natalia Mierzwa, Eliza Lutostańska, Jakub Szymanowski and Michalina Wężyk

Int. J. Mol. Sci. 2025, 26(23), 11242; https://doi.org/10.3390/ijms262311242 - 21 Nov 2025

Viewed by 439

Abstract

Pathogenic GRN variants that reduce progranulin (PGRN) levels cause frontotemporal dementia (FTD). To facilitate model development, we generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of two family members carrying the GRN c.1009C>T (p.Q337X) pathogenic variant—one symptomatic and one asymptomatic—as well as a non-carrier first-degree relative serving as a genetically matched control. The obtained iPSC lines were validated for pluripotency markers (Nanog, Sox2, Oct4, and TRA1-1-81), genomic integrity, and differentiation potential. The obtained iPSC lines were subsequently directed toward neuroepithelial stem (NES) cells. NES identity was confirmed by the expression of lineage-specific markers, including Nestin and Sox2 (assessed by immunocytochemistry), as well as SOX1, PLAGL1, and MKI67 (evaluated by real-time PCR). Furthermore, GRN mRNA levels were significantly reduced in iPSC and NES lines derived from mutation carriers compared to control cells. The established iPSC and NES cell lines represent a platform for modeling progranulin-deficient FTD. The symptomatic and asymptomatic carrier-derived lines obtained from the same family offer a unique opportunity to study disease progression across clinical phases. The control line, derived from a related (first-degree) non-carrier, minimizes genetic background variability. Their utility of the established cell lines extends to therapeutic drug screening and further differentiation into neuronal, non-neuronal, and organoid models. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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Review

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34 pages, 1389 KB

Open AccessReview

An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy

by Ekaterina Gornostal, Almaqdad Alsalloum, Egor Degtyarev, Ekaterina Kuznetsova, Aygun Levashova, Daria Mishina, Natalia Mingaleva, Ali Mazloum, Viktor Bogdanov, Julia Krupinova, Sergey Mikhalkov, Irina Rybkina, Olga Mityaeva and Pavel Volchkov

Int. J. Mol. Sci. 2025, 26(23), 11645; https://doi.org/10.3390/ijms262311645 - 1 Dec 2025

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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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18 pages, 2054 KB

Open AccessReview

Mild Cognitive Impairment and Sarcopenia: Effects of Resistance Exercise Training on Neuroinflammation, Cognitive Performance, and Structural Brain Changes

by Valeria Oporto-Colicoi, Alexis Sepúlveda-Lara, Gabriel Nasri Marzuca-Nassr and Paulina Sepúlveda-Figueroa

Int. J. Mol. Sci. 2025, 26(22), 11036; https://doi.org/10.3390/ijms262211036 - 14 Nov 2025

Cited by 1 | Viewed by 1136

Abstract

Mild cognitive impairment (MCI) and sarcopenia are prevalent age-related conditions that often coexist and share common mechanisms such as chronic inflammation, reduced neuroplasticity, and impaired muscle function. Resistance exercise training (RET) has emerged as a promising non-pharmacological strategy capable of addressing both physical and cognitive decline. The aim of this narrative review is to synthesize preclinical and clinical evidence on the effects of RET in older adults with MCI and sarcopenia, with a specific focus on its impact on neuroinflammation, cognitive performance and structural brain changes. At the molecular level, RET activates anabolic pathways, including PI3K/Akt/mTOR, enhances neurotrophic support via BDNF, NT-3, and IGF-1, and promotes hippocampal neurogenesis through exercise-induced myokines such as irisin and cathepsin B. RET also exerts immunomodulatory actions by shifting microglia toward anti-inflammatory M2 phenotypes, attenuating reactive astrogliosis, and supporting oligodendrocyte precursor cell differentiation, thereby improving myelin integrity. Neuroimaging studies consistently report preservation of hippocampal and precuneus gray matter, as well as improved white matter connectivity following RET. Clinically, RET has demonstrated significant and sustained improvements in executive function, memory, and global cognition, with effects persisting for up to 18 months. Collectively, RET represents a multifaceted intervention with the potential to delay progression from MCI to Alzheimer’s disease by integrating neuroprotective, anti-inflammatory, and anabolic effects. Standardization of RET protocols and identification of biomarkers of responsiveness are needed to optimize its role within multimodal dementia-prevention strategies. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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29 pages, 744 KB

Open AccessReview

Neurodegeneration Through the Lens of Bioinformatics Approaches: Computational Mechanisms of Protein Misfolding

by Mubashir Hassan, Saba Shahzadi, Ahmed A. Moustafa and Andrzej Kloczkowski

Int. J. Mol. Sci. 2025, 26(22), 11021; https://doi.org/10.3390/ijms262211021 - 14 Nov 2025

Viewed by 597

Abstract

Protein and peptide aggregation has become a prominent focus in biomedical research due to its critical role in the development of neurodegenerative diseases (NDs) and its relevance to industrial applications. Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are closely associated with abnormal aggregation processes, highlighting the need for a deeper understanding of their molecular mechanisms. In recent years, a wide range of computational methods, bioinformatics tools, and curated databases have been developed to predict and analyze sequences and structures that are prone to aggregation. These in silico approaches offer valuable insights into the underlying principles of aggregation and contribute to the identification of potential therapeutic targets. This review provides a concise overview of the current bioinformatics resources and computational techniques available for studying protein and peptide aggregation, intending to guide future research efforts in the field of neurodegenerative disease modeling and drug discovery. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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32 pages, 2479 KB

Open AccessReview

GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential

by Osama Sobhi Moaket, Sarah Eyad Obaid, Fawaz Eyad Obaid, Yusuf Abdulkarim Shakeeb, Samir Mohammed Elsharief, Afrin Tania, Radwan Darwish, Alexandra E. Butler and Abu Saleh Md Moin

Int. J. Mol. Sci. 2025, 26(21), 10743; https://doi.org/10.3390/ijms262110743 - 5 Nov 2025

Cited by 1 | Viewed by 3390

Abstract

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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Other

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13 pages, 1633 KB

Open AccessBrief Report

The Tetrapeptide HAEE Promotes Amyloid-Beta Clearance from the Brain

by Kristina A. Mukhina, Kseniya B. Varshavskaya, Aleksandra D. Rybak, Viktor V. Grishchenko, Elena V. Kuzubova, Mikhail V. Korokin, Olga I. Kechko and Vladimir A. Mitkevich

Int. J. Mol. Sci. 2025, 26(23), 11591; https://doi.org/10.3390/ijms262311591 - 29 Nov 2025

Viewed by 297

Abstract

Alzheimer’s disease is characterized by the accumulation of neurotoxic forms of amyloid-beta (Aβ) in the brain, leading to synaptic dysfunction, neuroinflammation, and neuronal death. The tetrapeptide HAEE crosses the blood–brain barrier (BBB), inhibits the formation of toxic Aβ oligomers, and reduces amyloid burden in vivo. However, the mechanisms of HAEE’s anti-amyloidogenic effect remained incompletely understood. In this study, we investigated the mechanism of HAEE-dependent Aβ clearance both in vitro and in vivo. Using ELISA, we assessed the HAEE effect on the levels of Aβ, IL-6, and TNFα in mouse brain tissue following intracerebroventricular administration. The mechanism of the anti-Aβ effect of HAEE was studied using primary brain cell cultures and a BBB transwell model through ELISA, flow cytometry, and microscopy. We showed that HAEE reduced Aβ level by 35% and IL-6 level by 40% in mouse brain tissue. HAEE enhanced Aβ clearance via LRP1- and PgP-dependent Aβ transport through the BBB and doubled the rate of Aβ degradation by microglia. In addition to inhibition of Aβ aggregation, HAEE dissolved already formed Aβ oligomers. The HAEE-induced decrease in IL-6 levels in the mouse brain was associated with reduced pro-inflammatory activation of microglia. Thus, HAEE’s effect against Aβ-related neuropathologies is realized through a decrease in the level of toxic Aβ oligomer and inhibition of neuroinflammation. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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