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Biomolecules
Special Issues
Pathogenesis and Neuropathology of Alzheimer's Disease
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Pathogenesis and Neuropathology of Alzheimer's Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 6237

Special Issue Editors

Dr. Venkata Atluri

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Meritus School of Osteopathic Medicine, Hagerstown, MD 21742, USA
Interests: HIV; NeuroAIDS; CRISPR gene-editing; Alzheimer’s disease; nanotechnology
Special Issues, Collections and Topics in MDPI journals
Dr. Fanpeng Zhao

E-Mail Website
Guest Editor
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
Interests: mitochondrial fragmentation; mitochondria-ER contacts; neurological disorders; RNA m6A modification; neuron-glia crosstalk
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most common form of dementia and the leading neurodegenerative disorder worldwide. It typically manifests as a decline in short-term memory and cognitive abilities, impairing daily functioning. While most AD cases are sporadic, a few hereditary forms have been identified, providing important genetic and neuropathological insights into its broader causes. The disease is characterized by synaptic loss and neuronal shrinkage, particularly in the hippocampus and cerebral cortex. Hallmarks of AD include amyloid plaques and neurofibrillary tau tangles—misfolded protein clumps scattered throughout the brain. Other pathological features of AD comprise abnormal microvasculature, mitochondrial dysfunction, interneuronal dysfunction, increased inflammatory response, elevated production of reactive oxygen species, impaired brain metabolism, dysregulated gene expression, etc. Alzheimer's disease is projected to become a significant public health crisis, and without effective interventions, it will impose considerable personal and economic burdens. Investigating the pathogenesis of AD is critical to identifying therapeutic targets that could lead to disease-modifying treatments. Neuropathological studies of presymptomatic or early symptomatic mutation carriers may offer valuable insights into the etiology of Alzheimer’s disease, similar to other neurodegenerative conditions.

The following Special Issue will explore the neuropathology of Alzheimer’s disease and present new insights into its pathogenesis. We will also showcase exceptional studies investigating predisposing factors leading to neuropathology and identifying early diagnostic markers and methods for AD diagnosis. We hope that this Special Issue will foster a deeper understanding of AD’s pathogenesis, early detection, and possible interventions.

Dr. Venkata Atluri
Dr. Fanpeng Zhao
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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • Alzheimer disease
  • pathogenesis
  • neuropathology
  • diagnosis
  • neurodegenerative diseases
  • microRNA as diagnostic marker
  • the important modulatory action of DNA repair enzyme DNA-PKcs in synaptic plasticity

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Published Papers (7 papers)

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Research

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13 pages, 374 KiB  
Article
Serum Npas-4 and Nptx-2 Levels in Alzheimer’s Disease: Potential Biomarkers of Synaptic Dysfunction in a Cross-Sectional Study
by Alev Lazoglu Ozkaya, Nilifer Gürbüzer, Tolga Mercantepe and Filiz Mercantepe
Biomolecules 2025, 15(6), 795; https://doi.org/10.3390/biom15060795 - 30 May 2025
Viewed by 267
Abstract
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal loss. Identifying reliable biomarkers for early diagnosis and disease monitoring remains a critical need. Objective: This study aimed to investigate the serum levels of NPAS-4 (Neuronal [...] Read more.
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal loss. Identifying reliable biomarkers for early diagnosis and disease monitoring remains a critical need. Objective: This study aimed to investigate the serum levels of NPAS-4 (Neuronal PAS Domain Protein 4) and NPTX-2 (Neuronal Pentraxin 2) in patients with Alzheimer’s disease, exploring their potential roles in disease pathophysiology and their relationship with lipid parameters. Methods: This was a cross-sectional study that included 63 patients diagnosed with Alzheimer’s disease and 56 age- and sex-matched healthy controls. Venous blood samples were collected from all participants. NPAS-4 and NPTX-2 levels were measured using the ELISA method, while lipid parameters were analyzed via spectrophotometric techniques. Cognitive assessment was performed using the Standardized Mini-Mental Test (SMMT). Comparative analyses between groups, correlation studies, logistic regression, and ROC analyses were conducted. Results: Serum NPAS-4 and NPTX-2 levels were significantly lower in Alzheimer’s patients compared to healthy controls (p < 0.001 and p = 0.001, respectively). Additionally, total cholesterol and LDL levels were lower in the patient group. Logistic regression analysis identified NPAS-4 as an independent risk predictor for Alzheimer’s disease (OR = 0.313, p < 0.001). ROC analyses demonstrated that both biomarkers had significant diagnostic discrimination power. However, no significant correlation was found between NPAS-4 and NPTX-2 levels and SMMT scores or lipid parameters. Conclusions: The decreased levels of NPAS-4 and NPTX-2 in Alzheimer’s patients may reflect biochemical manifestations of impaired synaptic plasticity. These findings suggest that NPAS-4 and NPTX-2 may serve as potential early biomarkers in the diagnosis and monitoring of Alzheimer’s disease. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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22 pages, 4981 KiB  
Article
A Novel Phosphorylated Tau Conformer Implicated in the Tauopathy Pathogenesis of Human Neurons
by Nahid Tofigh, Sadaf Agahi, Gholamhossein Riazi, Mahboobeh Ghalamkar Moazzam and Koorosh Shahpasand
Biomolecules 2025, 15(4), 585; https://doi.org/10.3390/biom15040585 - 15 Apr 2025
Viewed by 504
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cultures. These findings suggest the gauche pT231-tau conformer plays a key role in tau-mediated neurodegeneration and may be a potential therapeutic target for AD. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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14 pages, 2426 KiB  
Article
Identifying Hub Genes and miRNAs Associated with Alzheimer’s Disease: A Bioinformatics Pathway to Novel Therapeutic Strategies
by Elisa Gascón, Ana Cristina Calvo, Nora Molina, Pilar Zaragoza and Rosario Osta
Biomolecules 2024, 14(12), 1641; https://doi.org/10.3390/biom14121641 - 20 Dec 2024
Viewed by 1352
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting this disease are not yet known, and there is a lack of standardized biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, AD-affected brain tissue was analyzed using the GSE138260 dataset, identifying 612 differentially expressed genes (DEGs). Functional analysis revealed 388 upregulated DEGs associated with sensory perception and 224 downregulated DEGs linked to the regulation and modulation of synaptic processes. Protein–protein interaction network analysis identified 20 hub genes. Furthermore, miRNA target gene networks revealed 1767 miRNAs linked to hub genes, among which hsa-mir-106a-5p, hsa-mir-17-5p, hsa-mir-26a-5p, hsa-mir-27a-3p and hsa-mir-34a-5p were the most relevant. This study presents novel biomarkers and therapeutic targets for AD by analyzing the information obtained with a comprehensive literature review, providing new potential targets to study their role in AD. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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Review

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28 pages, 1703 KiB  
Review
Cytoskeletal Proteins and Alzheimer’s Disease Pathogenesis: Focusing on the Interplay with Tau Pathology
by Gege Jiang, Guanfeng Xie, Xiaoyi Li and Jing Xiong
Biomolecules 2025, 15(6), 831; https://doi.org/10.3390/biom15060831 - 6 Jun 2025
Viewed by 268
Abstract
The aggregation of Tau protein into neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease (AD), is associated with cognitive decline. Recent studies have revealed that neuronal cytoskeletal instability drives early AD pathogenesis. The physiological interaction between tau and the microtubule (MT) is crucial [...] Read more.
The aggregation of Tau protein into neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease (AD), is associated with cognitive decline. Recent studies have revealed that neuronal cytoskeletal instability drives early AD pathogenesis. The physiological interaction between tau and the microtubule (MT) is crucial for maintaining axonal transport and stability. However, aberrant post-translational modifications (PTMs) in the MT binding domain—such as phosphorylation, acetylation and ubiquitination—trigger tau dissociation, causing microtubule collapse, transport deficits, and synaptic dysfunction. MT dysregulation also affects actin/cofilin-mediated dendritic spine destabilization and causes the hyperplasia of the glial intermediate filament, which exacerbates neuroinflammation and synaptic toxicity. This review systematically explores the functions of neuronal cytoskeletons, deciphers the molecular crosstalk between tau pathology and cytoskeletal remodeling, and proposes multi-target therapeutic strategies to restore cytoskeletal homeostasis, thereby providing novel perspectives for precision interventions in AD Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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25 pages, 1948 KiB  
Review
The Role and Pathogenesis of Tau Protein in Alzheimer’s Disease
by Xiaoyue Hong, Linshu Huang, Fang Lei, Tian Li, Yi Luo, Mengliu Zeng and Zhuo Wang
Biomolecules 2025, 15(6), 824; https://doi.org/10.3390/biom15060824 - 5 Jun 2025
Viewed by 141
Abstract
Alzheimer’s disease (AD), a predominant neurodegenerative disorder, is clinically characterized by progressive cognitive deterioration and behavioral deficits. An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of [...] Read more.
Alzheimer’s disease (AD), a predominant neurodegenerative disorder, is clinically characterized by progressive cognitive deterioration and behavioral deficits. An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of AD involves two hallmark lesions: intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau aggregates and extracellular senile plaques containing amyloid-β (Aβ) peptide depositions. Although Aβ-centric research has dominated AD investigations over the past three decades, pharmacological interventions targeting Aβ pathology have failed to demonstrate clinical efficacy. Tau, a microtubule-associated protein predominantly localized to neuronal axons, orchestrates microtubule stabilization and axonal transport through dynamic tubulin interactions under physiological conditions. In AD pathogenesis, however, tau undergoes pathogenic post-translational modifications (PTMs), encompassing hyperphosphorylation, lysine acetylation, methylation, ubiquitination, and glycosylation. These PTM-driven alterations induce microtubule network disintegration, mitochondrial dysfunction, synaptic impairment, and neuroinflammatory cascades, ultimately culminating in irreversible neurodegeneration and progressive cognitive decline. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a framework for biomarker discovery, targeted therapeutic development, and precision medicine approaches in tauopathies. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a solid theoretical and experimental basis for the early diagnosis of neurodegenerative diseases, the discovery of therapeutic targets, and the development of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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18 pages, 1361 KiB  
Review
Inflammasome-Mediated Neuroinflammation: A Key Driver in Alzheimer’s Disease Pathogenesis
by Julie McGroarty, Shelbi Salinas, Hayden Evans, Bryan Jimenez, Vincent Tran, Samuel Kadavakollu, Arti Vashist and Venkata Atluri
Biomolecules 2025, 15(5), 676; https://doi.org/10.3390/biom15050676 - 7 May 2025
Viewed by 533
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly, characterized by memory loss, cognitive decline, and functional impairment. While hallmark pathological features include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence points [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly, characterized by memory loss, cognitive decline, and functional impairment. While hallmark pathological features include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence points to chronic neuroinflammation as a key driver of disease progression. Among inflammatory mechanisms, the activation of the NLRP3 (nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome in microglia plays a pivotal role by amplifying neuroinflammatory cascades, exacerbating synaptic dysfunction, and accelerating neuronal loss. This review examines the molecular underpinnings of AD with a focus on NLRP3 inflammasome-mediated neuroinflammation, detailing the crosstalk between Aβ, tau pathology, and innate immune responses. Finally, we highlight emerging therapeutic strategies targeting NLRP3 inflammasome activation as promising avenues for mitigating neuroinflammation and slowing AD progression. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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17 pages, 597 KiB  
Review
Navigating Alzheimer’s Disease Mouse Models: Age-Related Pathology and Cognitive Deficits
by Laura Maria De Plano, Alessandra Saitta, Salvatore Oddo and Antonella Caccamo
Biomolecules 2024, 14(11), 1405; https://doi.org/10.3390/biom14111405 - 5 Nov 2024
Cited by 3 | Viewed by 2212
Abstract
Since the mid-1990s, scientists have been generating mouse models of Alzheimer’s disease to elucidate key mechanisms underlying the onset and progression of the disease and aid in developing potential therapeutic approaches. The first successful mouse model of Alzheimer’s disease was reported in 1995 [...] Read more.
Since the mid-1990s, scientists have been generating mouse models of Alzheimer’s disease to elucidate key mechanisms underlying the onset and progression of the disease and aid in developing potential therapeutic approaches. The first successful mouse model of Alzheimer’s disease was reported in 1995 with the generation of the PDAPP mice, which were obtained by the overexpression of gene coding for the amyloid precursor protein (APP). Since then, scientists have used different approaches to develop other APP overexpression mice, mice overexpressing tau, or a combination of them. More recently, Saito and colleagues generated a mouse model by knocking in mutations associated with familial Alzheimer’s disease into the APP gene. In this review, we will describe the most used animal models and provide a practical guide for the disease’s age of onset and progression. We believe that this guide will be valuable for the planning and experimental design of studies utilizing these mouse models. Full article
(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)
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