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Unraveling the Molecular Mechanisms of Neurodegeneration
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Unraveling the Molecular Mechanisms of Neurodegeneration

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: 30 August 2025 | Viewed by 4273

Special Issue Editor

Dr. Michela Ferrucci

E-Mail Website
Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: neurodegeneration; spinal cord; motor neurons; glioblastoma; autophagy; light microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are among the leading causes of disability and death worldwide, primarily due to their impact on motor and cognitive functions. The incidence of these disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, is on the rise, mainly due to the aging population.

A variety of genetic and environmental factors have been identified as contributors to the pathogenesis of these diseases. Despite their distinct pathological mechanisms, neurodegenerative diseases share several common features, such as mitochondrial dysfunction, oxidative stress, aberrant exon splicing, and accumulation of misfolded/pathological proteins. Understanding these shared mechanisms that lead to the progressive loss of neurons remains one of the most significant challenges for neuroscientists today.

This Special Issue will collect scientific contributions that may enhance our understanding of established mechanisms or propose novel pathways involved in neuronal death. These insights will not only deepen our understanding of neurodegeneration but also provide new directions for developing future therapies to combat these devastating conditions.

Dr. Michela Ferrucci
Guest Editor

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Keywords

  • protein accumulation
  • mitochondria
  • genetic and epigenetic alterations
  • oxidative stress
  • apoptosis
  • autophagy

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Published Papers (4 papers)

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Research

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24 pages, 4602 KiB  
Article
GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer’s Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation
by Katrin Riemann, Jeldrik von Ahsen, Tamara Böhm, Martin Schlegel, Matthias Kreuzer, Thomas Fenzl, Hermann Russ, Christopher G. Parsons and Gerhard Rammes
Int. J. Mol. Sci. 2025, 26(9), 4167; https://doi.org/10.3390/ijms26094167 - 28 Apr 2025
Viewed by 598
Abstract
Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer’s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ [...] Read more.
Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer’s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ1–42, Aβ(p3-42), Aβ1–40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ1–42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the “tgArcSwe” AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD. Full article
(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Neurodegeneration)
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14 pages, 3693 KiB  
Article
Light-Sheet Fluorescence Imaging Reveals Three-Dimensional Amyloid Burden Reduction Following Five Weeks of Swimming Exercise in Alzheimer’s Mouse
by Hye Joo Son and Suk Hyun Lee
Int. J. Mol. Sci. 2025, 26(3), 1249; https://doi.org/10.3390/ijms26031249 - 31 Jan 2025
Viewed by 911
Abstract
Emerging evidence from observational studies suggests that lifestyle modifications, particularly moderate-intensity exercise, may confer neuroprotective benefits against dementia, potentially by enhancing brain resistance through clearance mechanisms. Using light-sheet fluorescence microscopy (LSFM) with tissue clearing, we investigated the role of voluntary swimming in ameliorating [...] Read more.
Emerging evidence from observational studies suggests that lifestyle modifications, particularly moderate-intensity exercise, may confer neuroprotective benefits against dementia, potentially by enhancing brain resistance through clearance mechanisms. Using light-sheet fluorescence microscopy (LSFM) with tissue clearing, we investigated the role of voluntary swimming in ameliorating β-amyloid pathology in a transgenic Alzheimer’s disease (AD) mouse model. Twenty 52-week-old hAPPsw mice were randomly divided into a 5-week voluntary swimming intervention group and a control group (each n = 10). Each session included a 10-min swim followed by a 10-min rest, escalating from one session per day in the first week to three sessions per day by the fifth week. The excised brains were prepared using tissue-clearing and volume immunostaining with thioflavin-S for β-amyloid. For LSFM imaging, the individual plaque area and volume, total plaque load, and morphological parameters were quantified via an Imaris-based three-dimensional (3D) volumetric surface model. Visual comparison revealed that the intervention group presented significantly lower β-amyloid accumulation. The total surface volume of β-amyloid accumulation in the intervention group was significantly lower than that of the control group (intervention, 122,180,948 μm3 [105,854,660–169,063,081]; control, 167,201,016 μm3 [139,367,765–193,535,450]; p = 0.043). There were no significant differences in the morphological parameters, such as ellipticity and sphericity. Our LSFM study demonstrated notable reductions in β-amyloid, as evidenced by a decrease in total surface volume, in 52-week-old transgenic mice after a 5-week structured swimming program, supporting the notion that even in advanced AD stages, leisure-time voluntary swimming serves as an efficacious intervention for augmenting resistance to pathology. Full article
(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Neurodegeneration)
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16 pages, 2521 KiB  
Article
A Reduction in Mitophagy Is Associated with Glaucomatous Neurodegeneration in Rodent Models of Glaucoma
by Renuka M. Chaphalkar, Bindu Kodati, Prabhavathi Maddineni, Shaoqing He, Calvin D. Brooks, Dorota L. Stankowska, Shaohua Yang, Gulab Zode and Raghu R. Krishnamoorthy
Int. J. Mol. Sci. 2024, 25(23), 13040; https://doi.org/10.3390/ijms252313040 - 4 Dec 2024
Cited by 1 | Viewed by 1260
Abstract
Glaucoma is a heterogenous group of optic neuropathies characterized by the degeneration of optic nerve axons and the progressive loss of retinal ganglion cells (RGCs), which could ultimately lead to vision loss. Elevated intraocular pressure (IOP) is a major risk factor in the [...] Read more.
Glaucoma is a heterogenous group of optic neuropathies characterized by the degeneration of optic nerve axons and the progressive loss of retinal ganglion cells (RGCs), which could ultimately lead to vision loss. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma, and reducing IOP remains the main therapeutic strategy. Endothelin-1 (ET-1), a potent vasoactive peptide, has been shown to produce neurodegenerative effects in animal models of glaucoma. However, the detailed mechanisms underlying ET-1-mediated neurodegeneration in glaucoma are not completely understood. In the current study, using a Seahorse Mitostress assay, we report that ET-1 treatment for 4 h and 24 h time points causes a significant decline in various parameters of mitochondrial function, including ATP production, maximal respiration, and spare respiratory capacity in cultured RGCs. This compromise in mitochondrial function could trigger activation of mitophagy as a quality control mechanism to restore RGC health. Contrary to our expectation, we observed a decrease in mitophagy following ET-1 treatment for 24 h in cultured RGCs. Using Morrison’s model of ocular hypertension in rats, we investigated here, for the first time, changes in mitophagosome formation by analyzing the co-localization of LC-3B and TOM20 in RGCs. We also injected ET-1 (24 h) into transgenic GFP-LC3 mice to analyze the formation of mitophagosomes in vivo. In Morrison’s model of ocular hypertension, as well as in ET-1 injected GFP-LC3 mice, we found a decrease in co-localization of LC3 and TOM20, indicating reduced mitophagy. Taken together, these results demonstrate that both ocular hypertension and ET-1 administration in rats and mice lead to reduced mitophagy, thus predisposing RGCs to neurodegeneration. Full article
(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Neurodegeneration)
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Review

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19 pages, 1143 KiB  
Review
The Role of α7-Nicotinic Acetylcholine Receptors in the Pathophysiology and Treatment of Parkinson’s Disease
by Eslam ElNebrisi, Yosra Lozon and Murat Oz
Int. J. Mol. Sci. 2025, 26(7), 3210; https://doi.org/10.3390/ijms26073210 - 30 Mar 2025
Viewed by 1035
Abstract
The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic [...] Read more.
The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, and influence dopamine release, positioning them as a promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering a superior therapeutic approach compared with direct agonists. Emerging preclinical studies suggest that α7-nAChR activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, and reduces neuroinflammation. Despite promising findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. This review underscores the significance of α7-nAChRs in PD pathophysiology and highlights future directions for their translational potential in neuroprotection and symptomatic relief. Full article
(This article belongs to the Special Issue Unraveling the Molecular Mechanisms of Neurodegeneration)
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