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Antioxidants
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Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease
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Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: 31 October 2025 | Viewed by 11015

Special Issue Editors

Dr. Marcello Leopoldo

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Guest Editor
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari, Bari, Italy
Interests: medicinal chemistry; serotonin receptors; dopamine receptors; formyl peptide receptors; positron emission tomography; fluorescent ligands
Special Issues, Collections and Topics in MDPI journals
Dr. Leonardo Brunetti

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Guest Editor Assistant
Università degli studi di Bari Aldo Moro, Bari, Italy
Interests: cell culture; transfection; cancer biology; pharmaceutical biotechnology; medicinal chemistry

Special Issue Information

Dear Colleagues,

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by a complex array of pathological factors, chiefly the deposition of amyloid β protein aggregates, which is accompanied by immune cell infiltration and neuroinflammation. This inflammatory process leads, in turn, to an overproduction of reactive oxygen and nitrogen species (ROS and RNS, respectively).

Researchers regularly debate the place of oxidative stress (OS) in the pathogenesis of AD, especially regarding its role as a cause or a consequence of neurodegenerative processes. While touted by some as promising therapeutic agents for AD, antioxidants are plagued by bioavailability issues that stifle their potential in this regard.

Thus, the picture is that of a highly dynamic topic of research on which much work remains to be carried out.

Hoping to provide our readers with an inspiring view on the topic, we invite you to submit your recent findings or a review article to our Special Issue centered on Alzheimer’s Disease.

Our goal is to gather the latest research on the role of OS in AD pathogenesis and the development of antioxidant compounds as potential AD therapeutics.

We welcome all approaches to studying AD pathophysiology.

We eagerly look forward to your contributions.

Dr. Marcello Leopoldo
Guest Editor

Dr. Leonardo Brunetti
Guest Editor Assistant

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Antioxidants 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 2900 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's disease
  • neuroinflammation
  • therapeutic agent
  • oxidative stress

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Published Papers (5 papers)

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22 pages, 1913 KiB  
Article
Investigating Bergamot Essential Oil (BEO) Properties: Cytoprotection in Neuronal Cells Exposed to Heavy Metals and Antibacterial Activities
by Alexia Barbarossa, Rosanna Mallamaci, Eleonora Spinozzi, Filippo Maggi, Maria Noemi Sgobba, Antonio Rosato, Alessia Carocci and Daniela Meleleo
Antioxidants 2025, 14(4), 400; https://doi.org/10.3390/antiox14040400 - 27 Mar 2025
Viewed by 353
Abstract
Bergamot [Citrus × limon (L.) Osbeck, syn. C. × bergamia (Risso) Risso & Poit.] is primarily cultivated in the Calabria region of Italy and exploited in the food and perfumery industry. The epicarp of its fruit is a rich source of essential [...] Read more.
Bergamot [Citrus × limon (L.) Osbeck, syn. C. × bergamia (Risso) Risso & Poit.] is primarily cultivated in the Calabria region of Italy and exploited in the food and perfumery industry. The epicarp of its fruit is a rich source of essential oil (BEO) containing mainly monoterpenes, which are known for their diverse biological activities, including antimicrobial, anti-inflammatory, antiproliferative, and neuromodulatory effects. Emerging evidence suggests that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, particularly Alzheimer’s disease (AD), where it contributes to neuronal dysfunction and cell death. Moreover, heavy metal exposure has been identified as a key environmental factor exacerbating oxidative stress and neurodegeneration in AD. This study aimed to explore whether BEO could mitigate heavy metal (Cd2+, Hg2+, and Pb2+)-induced neurotoxicity in SH-SY5Y cells, a model system for brain cells. MTT and calcein-AM assays were performed to examine the viability of the SH-SY5Y cells after exposure to each heavy metal itself, or in combination with BEO, whereas the LDH assay was carried out to determine the effects of BEO towards necrotic cell death induced by heavy metals. Furthermore, DCFH-DA was performed to determine whether BEO could protect SH-SY5Y from heavy metal-induced oxidative stress. This study also investigated the antibacterial properties of BEO on different Gram-positive and Gram-negative bacterial strains belonging to the ATCC collection. These results suggest that BEO may help counteract heavy metal-induced neuronal damage, particularly Cd2+ toxicity, potentially reducing one of the environmental risk factors associated with AD. Additionally, its antimicrobial properties reinforce its relevance in preventing infections that may contribute to neuroinflammation in AD. Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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15 pages, 1329 KiB  
Article
Preliminary Effects of American Elderberry Juice on Cognitive Functioning in Mild Cognitive Impairment Patients: A Secondary Analysis of Cognitive Composite Scores in a Randomized Clinical Trial
by Madison Musich, Ashley F. Curtis, Bradley J. Ferguson, David Drysdale, Andrew L. Thomas, C. Michael Greenlief, Joel I. Shenker and D. Q. Beversdorf
Antioxidants 2025, 14(2), 131; https://doi.org/10.3390/antiox14020131 - 23 Jan 2025
Viewed by 4137
Abstract
Previous work examining dietary interventions high in polyphenols (i.e., antioxidant/anti-inflammatory properties) has shown cognitive benefits. In a prior investigation examining American elderberry juice consumption with inflammation and cognition in mild cognitive impairment (MCI), we found a trend toward better visuospatial construct flexibility in [...] Read more.
Previous work examining dietary interventions high in polyphenols (i.e., antioxidant/anti-inflammatory properties) has shown cognitive benefits. In a prior investigation examining American elderberry juice consumption with inflammation and cognition in mild cognitive impairment (MCI), we found a trend toward better visuospatial construct flexibility in MCI patients who consumed elderberry relative to the placebo control. This study aims to further examine the preliminary effects of American elderberry juice on the cognitive domains in MCI using cognitive composite scores. MCI patients (N = 24; Mage = 76.33 ± 6.95) received elderberry (n = 11) or placebo (n = 13) juice for 6 months and completed cognitive tasks targeting memory, visuospatial ability, and cognitive flexibility at the baseline, 3 months, and 6 months. For the composite z-scores calculated for global cognition and each domain, multilevel models and Kenward–Roger post hoc tests examined the interaction between condition (elderberry/placebo) and time (baseline/3 months/6 months). The findings showed a significant interaction between global cognitive flexibility (p = 0.049) and elderberry juice (not the placebo) trending toward a significant decrease (better) in composite cognitive flexibility latency scores from the baseline (M = 29.89, SE = 18.12) to 6 months (M = 18.57, SE = 9.68). Preliminary findings suggest elderberry juice may provide overall cognitive flexibility benefits in MCI. These promising results provide support for prospective investigations examining the potential underlying mechanisms of elderberries that may provide cognitive benefits in MCI, possibly due to anti-inflammatory effects. Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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18 pages, 3431 KiB  
Article
Discovery of Effective Inhibitors Against Phosphodiesterase 9, a Potential Therapeutic Target of Alzheimer’s Disease with Antioxidant Capacities
by Qian Zhou, Xu-Nian Wu, Wei-Hao Luo, Qing-Hua Huang, Ling-Ling Feng, Yinuo Wu and Chen Zhang
Antioxidants 2025, 14(2), 123; https://doi.org/10.3390/antiox14020123 - 21 Jan 2025
Viewed by 755
Abstract
Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective [...] Read more.
Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess antioxidant activities. Molecular docking, together with dynamics simulations, were applied to accelerate compound design and reduce synthetic work. Four out of the 14 compounds were validated as effective PDE9 inhibitors with comparable antioxidant activity. Notably, compounds 17b and 17d demonstrated IC50 values of 91 and 89 nM against PDE9, respectively, with good antioxidant activities (ORAC (Trolox) of 2.00 and 2.60). This work provides a new approach for designing MTDLs for the treatment of AD and offers insights for further structural modifications of PDE9 inhibitors with antioxidant capacities. Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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23 pages, 3688 KiB  
Article
Ecklonia cava Ameliorates Cognitive Impairment on Amyloid β-Induced Neurotoxicity by Modulating Oxidative Stress and Synaptic Function in Institute of Cancer Research (ICR) Mice
by Hyo Lim Lee, Min Ji Go, Han Su Lee and Ho Jin Heo
Antioxidants 2024, 13(8), 951; https://doi.org/10.3390/antiox13080951 - 6 Aug 2024
Cited by 3 | Viewed by 2286
Abstract
This study investigated the neuroprotective effect of 70% ethanol extract of Ecklonia cava (EE) in amyloid beta (Aβ)-induced cognitive deficit mice. As a result of analyzing the bioactive compounds in EE, nine compounds were identified using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). [...] Read more.
This study investigated the neuroprotective effect of 70% ethanol extract of Ecklonia cava (EE) in amyloid beta (Aβ)-induced cognitive deficit mice. As a result of analyzing the bioactive compounds in EE, nine compounds were identified using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In particular, the diekcol content was quantified by high-performance liquid chromatography with diode-array detection (DAD-HPLC). Biochemical analysis was performed on brain tissue to determine the mechanism of the cognitive function improvement effect of EE. The result showed that EE ameliorated learning and memory decline in behavioral tests on Aβ-induced mice. EE also attenuated oxidative stress by regulating malondialdehyde (MDA) content, reduced glutathione (GSH), and superoxide dismutase (SOD) levels. Similarly, EE also improved mitochondrial dysfunction as mitochondrial membrane potential, ATP production, and reactive oxygen species (ROS) levels. In addition, EE enhanced synapse function by modulating acetylcholine-related enzymes and synaptic structural proteins in the whole brain, hippocampus, and cerebral cortex tissues. Also, EE regulated Aβ-induced apoptosis and inflammation through the c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways. Furthermore, EE protected neurotoxicity by increasing brain-derived neurotrophic factor (BDNF) production. These results suggest that EE may be used as a dietary supplement for the prevention and treatment of Alzheimer’s disease (AD). Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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12 pages, 1596 KiB  
Perspective
Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer’s Disease
by Suresh C. Tyagi
Antioxidants 2024, 13(10), 1225; https://doi.org/10.3390/antiox13101225 - 12 Oct 2024
Viewed by 2723
Abstract
Patients with Alzheimer’s disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive [...] Read more.
Patients with Alzheimer’s disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H2S. The repeat CAG expansion and m6A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut–brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H2S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H2S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H2S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting β-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits β-amyloid deposits by increasing the mitochondrial transsulfuration of H2S production. Full article
(This article belongs to the Special Issue Oxidative Stress as a Therapeutic Target of Alzheimer’s Disease)
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