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Molecular Mechanisms of Alzheimer’s Disease
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Molecular Mechanisms of 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: 31 August 2025 | Viewed by 2237

Special Issue Editor

Dr. Sudip Dhakal

E-Mail Website
Guest Editor
Health and Biosecurity, Commonwealth Scientific and Industrial Research Organization (CSIRO), Geelong, VIC 3220, Australia
Interests: Alzheimer’s disease; protein homeostasis; disease models; stress responses

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Despite decades of research, the precise molecular mechanisms driving AD pathogenesis are still incomplete, presenting significant challenges for early diagnosis and defining preventative strategies and effective therapeutic interventions. This Special Issue brings together cutting-edge research exploring the diverse molecular pathways involved in AD including the impairment of proteostasis, accumulation of amyloid plaques and neurofibrillary tau tangles, cellular stress response pathways, mitochondrial dysfunction, neuroinflammation, and cognitive decline.

This Special Issue features original research and review articles that deepen our understanding of these mechanisms, offering new perspectives on potential biomarkers, preventative strategies, and therapeutic strategies. By integrating multidisciplinary approaches, we aim to advance the field and pave the way for innovative interventions targeting the molecular underpinnings of AD. We invite researchers to explore these contributions and foster new collaborations in the fight against Alzheimer’s disease.

This Special Issue is supervised by Dr. Sudip Dhakal and assisted by Dr. Natalia Sowa-Rogozińska (Medical University of Gdansk).

Dr. Sudip Dhakal
Guest Editor

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
  • amyloid beta
  • tauopathy
  • autophagy
  • stress response
  • mitochondrial dysfunction
  • cognitive decline
  • biomarkers
  • disease models

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Published Papers (5 papers)

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Research

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22 pages, 3867 KiB  
Article
Neuroprotective Mechanisms of Porcine Brain Enzyme Hydrolysate in Memory Impairment: Multi-Target Strategy Against Amyloid-β-Induced Neurotoxicity
by Sun Myung Yoon, Ye-Won Lee, Min Ju Kim, Jae-Joon Shin, Gun Won Bae and Sunmin Park
Int. J. Mol. Sci. 2025, 26(13), 6030; https://doi.org/10.3390/ijms26136030 - 24 Jun 2025
Viewed by 338
Abstract
This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective [...] Read more.
This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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16 pages, 2715 KiB  
Article
Microneurotrophin BNN27 Exerts Significant Anti-Inflammatory Effects on Murine T-Lymphocytes Following CFA-Induced Inflammatory Pain
by Smaragda Poulaki, Aikaterini Kalantidou, Ioanna Lapi, Achille Gravanis and Maria Venihaki
Int. J. Mol. Sci. 2025, 26(12), 5498; https://doi.org/10.3390/ijms26125498 - 8 Jun 2025
Viewed by 408
Abstract
During tissue injury or infection, leukocytes are activated to produce proinflammatory mediators, which trigger the immune system to produce anti-inflammatory and analgesic molecules. Our previous studies provide evidence that synthetic microneurotrophins, like BNN27, exert significant analgesic and anti-inflammatory effects during Complete Freund’s Adjuvant [...] Read more.
During tissue injury or infection, leukocytes are activated to produce proinflammatory mediators, which trigger the immune system to produce anti-inflammatory and analgesic molecules. Our previous studies provide evidence that synthetic microneurotrophins, like BNN27, exert significant analgesic and anti-inflammatory effects during Complete Freund’s Adjuvant (CFA)-induced inflammation and pain. Thus, the aim of the present study was to examine if the effect of BNN27 on inflammatory pain is mediated at least in part by activation of T-lymphocytes. For this purpose, six hours following the injection of CFA, spleens were harvested in PBS and lymphocytes were collected and placed in medium containing concanavalin-A and IL-2 to prompt T-lymphocyte proliferation and differentiation. Cells were then treated with BNN27 at different concentrations and the media and cells were collected for ELISA and PCR assays. The proliferation rate of T-cells was also examined using the MTT assay. Our results showed that BNN27 significantly increased the proliferation of T-lymphocytes. In addition, BNN27 significantly decreased IL-6 and TNF-α protein levels, while it increased the mRNA expression of μ-opioid receptor and opioid peptides PENK and POMC at different time points. Our data demonstrate considerable anti-inflammatory and analgesic effects of BNN27, making it a promising molecule for inflammation and pain management. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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29 pages, 3276 KiB  
Article
Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer’s Disease: An Electrophysiological and Proteomic Analysis
by Beatriz Gil, Mairéad Sullivan, Caitriona Scaife, Jeffrey C. Glennon and Caroline Herron
Int. J. Mol. Sci. 2025, 26(10), 4944; https://doi.org/10.3390/ijms26104944 - 21 May 2025
Viewed by 642
Abstract
In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe/PS1dE9 (APP/PS1) mice. In wild-type [...] Read more.
In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe/PS1dE9 (APP/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 μM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (Aβ42). We also examined the effects of CBDA or vehicle in APP/PS1 mice and WT littermates over a 5-week period at 8 months. LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP/PS1 compared to vehicle-treated WT mice, while treatment of APP/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP/PS1 mice. Levels of cortical soluble Aβ42 were similar across CBDA- and vehicle-treated groups; however, the level of aggregated Aβ42 was decreased in the CBDA-treated group. Proteomic analysis of cortical tissue from APP/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP/PS1 mice. This research suggests that CBDA should be considered a novel therapy for AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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Review

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36 pages, 1414 KiB  
Review
A Systems Biology Approach to Memory Health: Integrating Network Pharmacology, Gut Microbiota, and Multi-Omics for Health Functional Foods
by Heng Yuan, Junyu Zhou, Hongbao Li, Suna Kang and Sunmin Park
Int. J. Mol. Sci. 2025, 26(14), 6698; https://doi.org/10.3390/ijms26146698 - 12 Jul 2025
Viewed by 154
Abstract
Memory impairment, ranging from mild memory impairment to neurodegenerative diseases such as Alzheimer’s disease, poses an escalating global health challenge that necessitates multi-targeted interventions to prevent progression. Health functional foods (HFFs), which include bioactive dietary compounds that not only provide basic nutrition but [...] Read more.
Memory impairment, ranging from mild memory impairment to neurodegenerative diseases such as Alzheimer’s disease, poses an escalating global health challenge that necessitates multi-targeted interventions to prevent progression. Health functional foods (HFFs), which include bioactive dietary compounds that not only provide basic nutrition but also function beyond that to modulate physiological pathways, offer a promising non-pharmacological strategy to preserve memory function. This review presents an integrative framework for the discovery, evaluation, and clinical translation of biomarkers responsive to HFFs in the context of preventing memory impairment. We examine both established clinical biomarkers, such as amyloid-β and tau in the cerebrospinal fluid, neuroimaging indicators, and memory assessments, as well as emerging nutritionally sensitive markers including cytokines, microRNAs, gut microbiota signatures, epigenetic modifications, and neuroactive metabolites. By leveraging systems biology approaches, we explore how network pharmacology, gut–brain axis modulation, and multi-omics integration can help to elucidate the complex interactions between HFF components and memory-related pathways such as neuroinflammation, oxidative stress, synaptic plasticity, and metabolic regulation. The review also addresses the translational pipeline for HFFs, from formulation and standardization to regulatory frameworks and clinical development, with an emphasis on precision nutrition strategies and cross-disciplinary integration. Ultimately, we propose a paradigm shift in memory health interventions, positioning HFFs as scientifically validated compounds for personalized nutrition within a preventative memory function framework. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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22 pages, 905 KiB  
Review
The Role of S6K1 in Aging and Alzheimer’s Disease: Mechanistic Insights and Therapeutic Potential
by Salvatore Oddo, Marika Lanza, Giovanna Casili and Antonella Caccamo
Int. J. Mol. Sci. 2025, 26(13), 5923; https://doi.org/10.3390/ijms26135923 - 20 Jun 2025
Viewed by 325
Abstract
Aging is the greatest risk factor for Alzheimer’s disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. [...] Read more.
Aging is the greatest risk factor for Alzheimer’s disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. S6K1 controls translation, autophagy, and mitochondrial function—processes disrupted in both aging and AD. This review examines how S6K1 influences mitochondrial metabolism, autophagy, and metabolic dysfunction in aging. We also discuss its role in the nervous system, including effects on synaptic plasticity, memory, glial activation, and neuroinflammation. In AD, S6K1 contributes to amyloid and tau pathology by regulating translation of BACE1 and tau, and its hyperactivation is linked to synaptic deficits and cognitive decline. We further explore therapeutic strategies targeting S6K1, which have shown benefits for lifespan extension and neuroprotection in preclinical models. Finally, we consider the emerging link between S6K1 and necroptosis, a form of programmed cell death implicated in AD-related neuronal loss. Together, these findings highlight S6K1 as a promising target for interventions aimed at slowing aging and mitigating AD pathogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)
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