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Molecular Insight into Alzheimer’s Disease
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Molecular Insight into Alzheimer’s Disease

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 July 2025 | Viewed by 4413

Special Issue Editors

Dr. Thierry Oster

E-Mail Website
Guest Editor
Nutrition-Génétique et Exposition aux Risques Environnementaux (N-GERE), Inserm U1256, Campus Brabois, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
Interests: brain aging; Alzheimer’s disease; neurodegenerative diseases; neuronal membranes; lipids; nutrition; membrane protein interactions; endocytosis; vesicular trafficking
Dr. Catherine Malaplate

E-Mail Website
Guest Editor
Nutrition-Génétique et Exposition aux Risques Environnementaux (N-GERE), Inserm U1256, Campus Brabois, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
Interests: brain aging; Alzheimer’s disease; neurodegenerative diseases; neuronal membranes; lipids; nutrition; membrane protein interactions; endocytosis; vesicular trafficking; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease is the most common form of dementia in the world. Identified as a neurodegenerative disease that mainly affects the elderly, it profoundly changes the functioning of the brain, thereby affecting cognitive functions such as memory to the point of threatening the autonomy of patients and altering their quality of life as well as that of those around them. These devastating consequences clearly pose a priority societal and public health issue.

The very active multidisciplinary research that began decades ago continues to explore many very diverse avenues, with the aim of contributing to improving diagnosis as well as the treatment and care of patients. Thousands of researchers around the world are still working today to better understand the causes of the disease, as well as the mechanisms involved in its onset and progression, particularly in order to identify preventive or curative therapeutic solutions.

The aim of this Special Issue is to bring together some of the most recent and convincing advances in the cellular and molecular mechanisms associated with Alzheimer’s disease, without bias or a priori on the hypotheses developed. This Special Issue will accept original studies as well as reviews.

Dr. Thierry Oster
Dr. Catherine Malaplate
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.

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Keywords

  • Alzheimer’s disease
  • cellular and molecular mechanisms
  • neuronal membranes, endocytosis, and vesicular trafficking
  • molecular crosstalk between neurons and glial cells
  • protein interaction with lipids or other proteins
  • biomarkers and diagnosis
  • epidemiology, risk factors, and prevention
  • therapeutic visions

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Published Papers (5 papers)

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Research

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18 pages, 2292 KiB  
Article
Comprehensive Anatomical Staging Predicts Clinical Progression in Mild Cognitive Impairment: A Data-Driven Approach
by Raghav Tandon, Yajun Mei, James J. Lah and Cassie S. Mitchell
Int. J. Mol. Sci. 2025, 26(12), 5514; https://doi.org/10.3390/ijms26125514 - 9 Jun 2025
Viewed by 296
Abstract
Alzheimer’s disease (AD) presents significant challenges in clinical practice due to its heterogeneous manifestation and variable progression rates. This work develops a comprehensive anatomical staging framework to predict progression from mild cognitive impairment (MCI) to AD. Using the ADNI database, the scalable Subtype [...] Read more.
Alzheimer’s disease (AD) presents significant challenges in clinical practice due to its heterogeneous manifestation and variable progression rates. This work develops a comprehensive anatomical staging framework to predict progression from mild cognitive impairment (MCI) to AD. Using the ADNI database, the scalable Subtype and Stage Inference (s-SuStaIn) model was applied to 118 neuroanatomical features from cognitively normal (n = 504) and AD (n = 346) participants. The framework was validated on 808 MCI participants through associations with clinical progression, CSF and FDG-PET biomarkers, and neuropsychiatric measures, while adjusting for common confounders (age, gender, education, and APOE ε4 alleles). The framework demonstrated superior prognostic accuracy compared to traditional risk assessment (C-index = 0.73 vs. 0.62). Four distinct disease subtypes showed differential progression rates, biomarker profiles (FDG-PET and CSF Aβ42), and cognitive trajectories: Subtype 1, subcortical-first pattern; Subtype 2, executive–cortical pattern; Subtype 3, disconnection pattern; and Subtype 4, frontal–executive pattern. Stage-dependent changes revealed systematic deterioration across diverse cognitive domains, particularly in learning acquisition, visuospatial processing, and functional abilities. This data-driven approach captures clinically meaningful disease heterogeneity and improves prognostication in MCI, potentially enabling more personalized therapeutic strategies and clinical trial design. Full article
(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)
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18 pages, 2307 KiB  
Article
Dementia from Small Vessel Disease Versus Alzheimer’s Disease: Separate Diseases or Distinct Manifestations of Cerebral Capillopathy Due to Blood–Brain Barrier Dysfunction? A Pilot Study
by Charles R. Joseph, Davis A. Melin, Lindsay K. Wanner, Bryant Hartman, Jason Badelita, Lucy C. Conser, Harrison D. Kline, Pranav M. Pradhan and Kim Love
Int. J. Mol. Sci. 2025, 26(11), 5040; https://doi.org/10.3390/ijms26115040 - 23 May 2025
Viewed by 375
Abstract
Pathophysiological differences separating small vessel disease (SVD) from Alzheimer’s disease (AD) may alter treatment approach. Investigating peak-arterial and late-capillary perfusion may differentiate SVD from AD. 14 Subjects with MoCA scores of 11–24 were divided into 2 groups. Group one: 6 AD likely subjects [...] Read more.
Pathophysiological differences separating small vessel disease (SVD) from Alzheimer’s disease (AD) may alter treatment approach. Investigating peak-arterial and late-capillary perfusion may differentiate SVD from AD. 14 Subjects with MoCA scores of 11–24 were divided into 2 groups. Group one: 6 AD likely subjects positive for 1 or 2 copies of APOE 4+. Group two: 8 SVD likely subjects APOE−. Group three: 7 age-matched controls (MoCA 26–30). All underwent 3D PASL MRI, FLAIR, and SWI axial MRI. Arterial phase peak amplitude and latency, late capillary inflow/clearance rates, and anatomic abnormalities quantitated using microhemorrhage count, Fazekas, Koedam, and Schelton scales were compared. Arterial perfusion demonstrated no statistical differences among SVD, AD, and controls, suggesting normal arterial flow. Late phase perfusion showed significant localized reduction in capillary flow/clearance rates in SVD and AD compared to controls. Absent arterial phase but significant capillary inflow/clearance differences from controls suggest SVD and AD share common impaired blood–brain barrier origins. Full article
(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)
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18 pages, 3477 KiB  
Article
Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment
by Pavel E. Volynsky, Anatoly S. Urban, Konstantin V. Pavlov, Yaroslav V. Bershatsky, Olga V. Bocharova, Anastasia K. Kryuchkova, Veronika V. Zlobina, Alina A. Gavrilenkova, Sofya M. Dolotova, Anna V. Kamynina, Olga T. Zangieva, Amir Taldaev, Oleg V. Batishchev, Ivan S. Okhrimenko, Tatiana V. Rakitina, Roman G. Efremov and Eduard V. Bocharov
Int. J. Mol. Sci. 2025, 26(2), 553; https://doi.org/10.3390/ijms26020553 - 10 Jan 2025
Cited by 1 | Viewed by 1170
Abstract
Alzheimer’s disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the [...] Read more.
Alzheimer’s disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the APP and secretase location relative to ordered or disordered membrane microdomains. We used high-resolution NMR to probe the interactions of the cholesterol analog with APP transmembrane domain in two membrane-mimicking systems resembling ordered or perturbed lipid environments (bicelles/micelles). In bicelles, spin-labeled sterol interacted with the peptide near the amphiphilic juxtamembrane region and N-terminal part of APP transmembrane helix, as described earlier for cholesterol. Upon transition into micellar environment, another interaction site appeared where sterol polar head was buried in the hydrophobic core near the hinge region. In MD simulations, sterol moved between three interaction sites, sliding along the polar groove formed by glycine residues composing the dimerization interfaces and flexible hinge of the APP transmembrane domain. Because the lipid environment modulates interactions, the role of lipids in the AD pathogenesis is defined by the state of the entire lipid subsystem rather than the effects of individual lipid species. Cholesterol can interplay with other lipids (polyunsaturated, gangliosides, etc.), determining the outcome of amyloid-β production cascades. Full article
(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)
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Review

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26 pages, 2448 KiB  
Review
Iron-Mediated Overexpression of Amyloid Precursor Protein via Iron Responsive mRNA in Alzheimer’s Disease
by Mateen A. Khan
Int. J. Mol. Sci. 2025, 26(11), 5283; https://doi.org/10.3390/ijms26115283 - 30 May 2025
Viewed by 342
Abstract
Iron accumulation in the brain is widespread in Alzheimer’s disease (AD), the most common cause of dementia. According to numerous studies, too much iron triggers the development of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques, both of which accelerate the onset of AD. [...] Read more.
Iron accumulation in the brain is widespread in Alzheimer’s disease (AD), the most common cause of dementia. According to numerous studies, too much iron triggers the development of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques, both of which accelerate the onset of AD. Iron sequestration and storage were disrupted by high iron, and the pattern of interaction between iron regulatory proteins (IRPs) and iron-responsive elements (IREs) was altered. The 5′-untranslated regions (5′-UTRs) of their APP mRNA transcripts have an IRE stem-loop, which is where iron influx enhances the translation of the amyloid precursor protein (APP). Iron regulated APP expression via the release of the repressor interaction of APP mRNA with IRP1 by a pathway similar to the iron control translation of the ferritin mRNA by the IREs in their 5′-UTRs. This leads to an uncontrolled buildup of redox active Fe2+, which exacerbates neurotoxic oxidative stress and neuronal death. Fe2+ overload upregulates the APP expression and increases the cleavage of APP and the accumulation of Aβ in the brain. The level of APP and Aβ, and protein aggregates, can be downregulated by IRPs, but are upregulated in the presence of iron overload. Therefore, the inhibition of the IRE-modulated expression of APP or Fe2+ chelation offers therapeutic significance to AD. In this article, I discuss the structural and functional features of IRE in the 5′-UTR of APP mRNA in relation to the cellular Fe2+ level, and the link between iron and AD through the amyloid translational mechanism. Although there are currently no treatments for AD, a progressive neurodegenerative disease, there are a number of promising RNA inhibitor and Fe2+ chelating agent therapeutic candidates that have been discovered and are being validated in April 2025 clinical trials. Future studies are expected to further show the therapeutic efficacy of iron-chelating medications, which target the APP 5′-UTR and have the ability to lower APP translation and, consequently, Aβ levels. As a result, these molecules have a great deal of promise for the development of small-molecule RNA inhibitors for the treatment of AD. Full article
(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)
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12 pages, 2159 KiB  
Review
Molecular Roles of NADPH Oxidase-Mediated Oxidative Stress in Alzheimer’s Disease: Isoform-Specific Contributions
by Junhyung Kim and Jong-Seok Moon
Int. J. Mol. Sci. 2024, 25(22), 12299; https://doi.org/10.3390/ijms252212299 - 15 Nov 2024
Cited by 2 | Viewed by 1725
Abstract
Oxidative stress is linked to the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder marked by memory impairment and cognitive decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau. AD is [...] Read more.
Oxidative stress is linked to the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder marked by memory impairment and cognitive decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau. AD is associated with an imbalance in redox states and excessive reactive oxygen species (ROS). Recent studies report that NADPH oxidase (NOX) enzymes are significant contributors to ROS generation in neurodegenerative diseases, including AD. NOX-derived ROS aggravates oxidative stress and neuroinflammation during AD. In this review, we provide the potential role of all NOX isoforms in AD pathogenesis and their respective structural involvement in AD progression, highlighting NOX enzymes as a strategic therapeutic target. A comprehensive understanding of NOX isoforms and their inhibitors could provide valuable insights into AD pathology and aid in the development of targeted treatments for AD. Full article
(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)
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