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Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments
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Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 16057

Special Issue Editors

Dr. Luisa Agnello

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Guest Editor
Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Clinical Laboratory Medicine, University of Palermo, 90127 Palermo, Italy
Interests: biomarkers; neurodegenerative diseases; Alzheimer's disease; multiple sclerosis; vitamin D; neurodegeneration; Parkinson’s disease; laboratory medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Maria Ciaccio

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Guest Editor
Internal Medicine and Stroke Care Ward, Department ProMISE “G. D’Alessandro", University of Palermo, 90127 Palermo, Italy
Interests: neurological disorders; biomarkers; ischemic stroke; multiple sclerosis; synaptic dysfunction; exosomal miRNAs; DNA binding protein; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases (ND) are a heterogeneous group of disorders characterized by the progressive dysfunction and loss of neurons in different areas of the central or peripheral nervous system. NDs represent a big challenge for scientific research due to their prevalence, cost and unknown pathophysiological mechanisms and the lack of mechanism-based treatments. 

An ND patient’s care pathway, from screening to diagnosis, prognosis and monitoring, is complex and relies mainly on clinical criteria. However, especially in the early stages, NDs have overlapping signs and symptoms leading to delayed diagnosis. Thus, tools are urgently needed to support clinicians in the early and appropriate management of NDs. In recent decades, significant advances have been made, but further efforts are mandatory in the field of ND research. 

This Special Issue aims to collect research articles and literature reviews in the field of ND research, including Dementia, Multiple Sclerosis, Amyotrophic Lateral Sclerosis and Parkinson’s disease, to unravel molecular mechanisms underpinning their pathogeneses and new molecular biomarkers, with a focus on the role of inflammation. Indeed, in recent decades, evidence from several studies supports the pivotal role of inflammation in ND pathogenesis.

Dr. Luisa Agnello
Dr. Anna Maria Ciaccio
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegeneration
  • inflammation
  • biomarkers
  • Alzheimer’s disease
  • molecular mechanism
  • pathogenesis

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Published Papers (6 papers)

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Research

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22 pages, 958 KB  
Article
Potential Neuroprotective Role of GLP-2 in Alzheimer’s Disease: Clinical Observations, Mechanistic Insights, and Comparison with GLP-1
by Maciej Czarnecki, Agnieszka Baranowska-Bik, Anna Litwiniuk, Małgorzata Kalisz, Anita Domańska, Anna Kurdyła and Wojciech Bik
Int. J. Mol. Sci. 2026, 27(3), 1609; https://doi.org/10.3390/ijms27031609 - 6 Feb 2026
Cited by 1 | Viewed by 893
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by progressive cognitive decline, β-amyloid accumulation, tau pathology, oxidative stress, and neuroinflammation. Increasing evidence suggests that metabolic dysregulation may contribute to AD pathogenesis. Glucagon-like peptide-2 (GLP-2), an intestinal peptide hormone, [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by progressive cognitive decline, β-amyloid accumulation, tau pathology, oxidative stress, and neuroinflammation. Increasing evidence suggests that metabolic dysregulation may contribute to AD pathogenesis. Glucagon-like peptide-2 (GLP-2), an intestinal peptide hormone, has demonstrated neuroprotective effects in preclinical models, potentially through anti-inflammatory and anti-apoptotic mechanisms. However, its role in human neurodegenerative disorders remains insufficiently understood. This study aimed to compare plasma GLP-2 concentrations between individuals with AD and cognitively healthy controls and to examine associations between GLP-2 levels, cognitive impairment severity, and metabolic parameters. Sixty-one patients with clinically diagnosed AD and twenty-three cognitively unimpaired controls were recruited. Plasma total GLP-2 concentrations were assessed at baseline in all participants and additionally at 6 and 12 months in a subgroup of 34 AD patients. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. Group comparisons, subgroup analyses based on AD severity, repeated-measures analyses, Spearman correlations, and multivariable linear regression models (including age and clinical group) were performed. Plasma GLP-2 concentrations were significantly higher in AD patients than in controls, with a moderate effect size (Cohen’s d ≈ 0.60). In severity-based subgroup analyses, both the mild and moderate-to-severe AD groups showed significantly higher GLP-2 levels than controls. Longitudinal analyses in AD patients (n = 34) showed no significant changes in GLP-2 concentrations over 12 months. Cognitive performance declined over time, with a significant reduction in MMSE from baseline to 6 months, whereas GLP-2 levels were not correlated with MMSE or CDR at any time point. GLP-2 levels correlated positively with body mass index (BMI), body weight, insulin, and HOMA-IR. In multivariable regression analysis, neither age nor clinical group independently predicted GLP-2 concentrations (both p > 0.05). Plasma GLP-2 concentrations were higher in patients with AD than in cognitively healthy controls; however, GLP-2 levels were not associated with cognitive performance or its progression over 12 months. GLP-2 was positively related to markers of adiposity and insulin resistance, suggesting stronger links to metabolic status than to cognitive severity. Further studies are needed to clarify whether GLP-2 alterations in AD reflect compensatory mechanisms, metabolic factors, or disease-related pathophysiology. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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19 pages, 1543 KB  
Article
Peripheral Leukocyte Syndecan-3 Is Elevated in Alzheimer’s Disease: Evidence from a Human Study
by Anett Hudák, Annamária Letoha and Tamás Letoha
Int. J. Mol. Sci. 2025, 26(14), 6587; https://doi.org/10.3390/ijms26146587 - 9 Jul 2025
Cited by 1 | Viewed by 1972
Abstract
Syndecan-3 (SDC3), a transmembrane heparan sulfate proteoglycan involved in cell signaling and endocytosis, has recently been implicated in the pathogenesis of neurodegenerative disorders. While preclinical studies have demonstrated its role in Alzheimer’s disease (AD), its diagnostic relevance in peripheral blood remains unexplored. In [...] Read more.
Syndecan-3 (SDC3), a transmembrane heparan sulfate proteoglycan involved in cell signaling and endocytosis, has recently been implicated in the pathogenesis of neurodegenerative disorders. While preclinical studies have demonstrated its role in Alzheimer’s disease (AD), its diagnostic relevance in peripheral blood remains unexplored. In this human cohort study, we measured SDC3 expression in peripheral blood mononuclear cells (PBMCs) from 22 clinically diagnosed AD patients and 20 cognitively unimpaired non-AD controls using a custom ELISA. The findings were compared with plasma p-tau217 levels and a panel of systemic laboratory markers. PBMC-expressed SDC3 was significantly elevated in AD patients and moderately correlated with AD status (r = 0.309, p = 0.0465) independent of age. Notably, SDC3 levels were inversely correlated with systemic inflammatory markers, including C-reactive protein (CRP; r = −0.421, p = 0.0055) and D-dimer (r = −0.343, p = 0.038), suggesting an AD-associated immune phenotype distinct from acute-phase or vascular inflammation. Conversely, plasma p-tau217 levels did not significantly differ between groups but correlated with markers of tissue injury and inflammation (LDH, GOT, and ferritin), potentially reflecting systemic influences in non-AD controls. A multivariable logistic regression model incorporating SDC3, p-tau217, and age demonstrated high diagnostic accuracy (AUC = 0.85). These findings identify PBMC-expressed SDC3 as a promising blood-based biomarker candidate for AD, warranting further validation in larger, biomarker-confirmed cohorts. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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Review

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27 pages, 1957 KB  
Review
Connecting the Dots: Neurobiological Interplay Between Type 2 Diabetes and Alzheimer’s Disease
by Analía Foncea-Bitrán, Cristián Barros-Osorio, Francisca Arriaza, Catalina Ramírez-López, Lina M. Ruiz, Marlen Barreto, Fernando C. Ortiz, Francisca Cornejo and Gonzalo I. Gómez
Int. J. Mol. Sci. 2026, 27(7), 3225; https://doi.org/10.3390/ijms27073225 - 2 Apr 2026
Viewed by 774
Abstract
Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates [...] Read more.
Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer’s disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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12 pages, 3397 KB  
Review
Cutaneous α-Synuclein and Age Spots in Neurodegeneration: A Systematic Review and Testable Hypothesis
by Arianna Di Stadio, Pietro De Luca, Beatrice Francavilla, Massimo Ralli, Stefano Di Girolamo, Iole Indovina, Giulia Ciccarese and Laura Dipietro
Int. J. Mol. Sci. 2026, 27(1), 96; https://doi.org/10.3390/ijms27010096 - 22 Dec 2025
Viewed by 756
Abstract
Recent studies have identified phosphorylated α-synuclein in the skin of individuals with neurodegenerative disease. The levels of this protein in the skin have been correlated with disease severity. This protein has been specifically studied in alpha-synucleinopathies such as Parkinsons’ Disease (PD) and Multiple [...] Read more.
Recent studies have identified phosphorylated α-synuclein in the skin of individuals with neurodegenerative disease. The levels of this protein in the skin have been correlated with disease severity. This protein has been specifically studied in alpha-synucleinopathies such as Parkinsons’ Disease (PD) and Multiple System Atrophy (MSA). Given that skin biopsy studies have often shown high levels of phosphorylated α-synuclein in the neck area, and that other clinical studies have described easily identifiable changes in facial skin features, this systematic review explores whether age spots, which are very common in sun-exposed areas (hands and face), could serve as early indicators of neurodegenerative disease. We performed a systematic review of the literature in three databases (Google, Scopus and Pubmed) following PRISMA guidelines. We used the following keywords: “alpha-synuclein and skin”, “alpha-synuclein and skin spots”, “alpha-synuclein and solar lentigo”, “alpha-synuclein and age spots”, “alpha-synuclein and melanocytes”, “skin biopsy and synucleinopathies”, “skin biopsy and neurodegenerative disease”, and “Parkinson’s Disease. Eleven studies were identified and included. Based on the study results and preliminary evidence in the literature evaluating the effect of α-synuclein on keratinocytes and melanocytes, we propose that the accumulation of this protein within the skin may produce visible alterations that can be quantified to enable early, noninvasive detection of neurodegenerative disease. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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26 pages, 755 KB  
Review
Surrogate Biomarkers in Gene Therapy for Orphan Diseases: Validation, Application, and Regulatory Aspects
by Aisylu I. Ayupova, Valeriya V. Solovyeva, Shaza S. Issa, Haidar J. Fayoud and Albert A. Rizvanov
Int. J. Mol. Sci. 2025, 26(20), 10107; https://doi.org/10.3390/ijms262010107 - 17 Oct 2025
Cited by 3 | Viewed by 3042
Abstract
The development of gene therapies for rare hereditary disorders is hindered by small patient cohorts, incomplete characterization of natural disease history, and the impracticality of conducting long-term clinical trials. Surrogate biomarkers—quantifiable indicators predictive of clinical outcomes—represent a promising strategy to accelerate the evaluation [...] Read more.
The development of gene therapies for rare hereditary disorders is hindered by small patient cohorts, incomplete characterization of natural disease history, and the impracticality of conducting long-term clinical trials. Surrogate biomarkers—quantifiable indicators predictive of clinical outcomes—represent a promising strategy to accelerate the evaluation of therapeutic efficacy. This review examines the role of surrogate endpoints in gene therapy, outlining essential validation criteria, including biological plausibility, analytical reproducibility, and clinical predictive value. Regulatory frameworks governing surrogate markers in the United States, European Union, Russia, Japan, China, and Canada are compared, with emphasis on mechanisms for expedited or conditional approval. Challenges associated with biomarker validation and extrapolation in the context of rare diseases are discussed, alongside future perspectives that integrate multi-omics technologies and artificial intelligence to enhance biomarker discovery and facilitate regulatory acceptance. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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21 pages, 1337 KB  
Review
Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice
by Luisa Agnello, Caterina Maria Gambino, Anna Maria Ciaccio, Anna Masucci, Roberta Vassallo, Martina Tamburello, Concetta Scazzone, Bruna Lo Sasso and Marcello Ciaccio
Int. J. Mol. Sci. 2024, 25(8), 4323; https://doi.org/10.3390/ijms25084323 - 13 Apr 2024
Cited by 22 | Viewed by 7126
Abstract
Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system’s cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine [...] Read more.
Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system’s cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine could support clinicians in detecting and differentiating NDs. Indeed, biomarkers could indicate the pathological mechanisms underpinning NDs. The ideal biofluid for detecting the biomarkers of NDs is cerebrospinal fluid (CSF), which has limitations, hampering its widespread use in clinical practice. However, intensive efforts are underway to introduce high-sensitivity analytical methods to detect ND biomarkers in alternative nonivasive biofluid, such as blood or saliva. This study presents an overview of the ND molecular biomarkers currently used in clinical practice. For some diseases, such as Alzheimer’s disease or multiple sclerosis, biomarkers are well established and recommended by guidelines. However, for most NDs, intensive research is ongoing to identify reliable and specific biomarkers, and no consensus has yet been achieved. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases and Inflammation: Pathogenesis, Biomarkers and Treatments)
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