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Cited by 194Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchRedox biology and oxidative stress

Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer’s Disease: Role of Glutathione and Metal Ions

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Roy, Rimil Guha, Mandal, Pravat K, Maroon, Joseph C.·2023·ACS Chemical Neuroscience
DOI 10.1021/acschemneuro.3c00486PMC PMC10485904
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Abstract

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aβ) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aβ in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aβ deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

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  • Transition metals (iron, copper, zinc) and Aβ-metal complexes act as potent redox catalysts, amplifying free radical production.

    “while transition metals (iron, copper, zinc) and Aβ–metal complexes act as potent redox catalysts, amplifying free radical production [103].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [103]

    The Introduction’s “Role of Metal Ions in AD” section says free Cu and Fe catalyze reactive oxygen species production and that Cu–Aβ complexes catalyze H2O2 formation. It discusses Zn in relation to Aβ aggregation, but does not say Zn or Zn–Aβ complexes catalyze free-radical production; the claim extends the redox-catalyst finding to zinc. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ROS-induced activation of microglia and astrocytes fuels a chronic neuroinflammatory response.

    “Furthermore, ROS-induced activation of microglia and astrocytes fuels a chronic neuroinflammatory response, while transition metals (iron, copper, zinc) and Aβ–metal complexes act as potent redox catalysts, amplifying free radical production [103].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [103]

    The Introduction’s “Role of Reactive Oxygen Species in AD” section links microglial activation to a neuroinflammatory enzyme that produces ROS. It does not say that ROS activates microglia or astrocytes, or that their activation sustains a chronic neuroinflammatory response; the causal direction it describes is different. Page numbers were not available in our copy. (LLM, conf=0.77)

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Cited by

Sorted by citations

Authors
Roy, R. G., Mandal, P. K., & Maroon, J. C.
Affiliations
  • National Brain Research Centre (IN)
  • Florey Institute of Neuroscience and Mental Health (AU)
  • University of Pittsburgh (US)
Corresponding author
Mandal, Pravat K
ORCID
Venue
ACS Chemical Neuroscience
Publisher
American Chemical Society (ACS)
Published
2023-08-10
Volume
14
Issue
17
Pages
2944-2954
ISSN
1948-7193 (ISSN-L)
DOI
10.1021/acschemneuro.3c00486
PMC
PMC10485904
OpenAlex
W4385717114
Cited by
194
References
23
Citations by year
2026: 72 · 2025: 65 · 2024: 52 · 2023: 5
FWCI
6.50
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Chemical Neuroscience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Biotechnology Industry Research Assistance Council (4(5)/201-ITEA)
  • Australia-India Strategic Research Fund (BT/Indo-Aus/10/31/2016/PKM)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
Alzheimer's disease, oxidative stress, amyloid plaques, tau hyperphosphorylation, glutathione, metal ions, iron chelation, neurofibrillary tangles, antioxidant therapy, amyloid-beta oligomers, pathogenesis
MeSH terms
Alzheimer Disease, Antioxidants, Glutathione, Humans, Metals, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Oxidative Stress, Plaque, Amyloid

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