Cognitive impairment in humanized APP×PS1 mice is linked to Aβ1–42 and NOX activation

Bruce-Keller, Annadora J.; Gupta, Sunita; Knight, Alecia G.; Beckett, Tina L.; McMullen, Jessica M.; Davis, Paulina R.; Murphy, M. Paul; Van Eldik, Linda J.; St Clair, Daret; Keller, Jeffrey N.

doi:10.1016/j.nbd.2011.07.012

Cited by 97Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchRedox biology and oxidative stress

Cognitive impairment in humanized APP×PS1 mice is linked to Aβ1–42 and NOX activation

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Bruce-Keller, Annadora J., Gupta, Sunita, Knight, Alecia G., Beckett, Tina L., McMullen, Jessica M., Davis, Paulina R., Murphy, M. Paul, Van Eldik, Linda J. +2 more·2011·Neurobiology of Disease

DOI 10.1016/j.nbd.2011.07.012PMC PMC3185143

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Abstract

Cognitive impairment in Alzheimer's disease (AD) is strongly associated with both extensive deposition of amyloid β peptides and oxidative stress, but the exact role of these indices in the development of dementia is not clear. This study was designed to determine the relationship between cognitive impairment, activation of the free radical producing enzyme NADPH oxidase (NOX), and progressive changes in Aβ deposition and solubility in humanized APP×PS1 knock-in mice of increasing age. Data show that cognitive performance and expression of key synaptic proteins were progressively decreased in aging APP×PS1 mice. Likewise, NOX activity and expression of the specific NOX subunit NOX4 were significantly increased in APP×PS1 mice in an age-dependent manner, and NOX activity and cognitive impairment shared a significant linear relationship. Data further show that age-dependent increases in Aβ(1-42) had a significant linear relationship with both NOX activity and cognitive performance in APP×PS1 knock-in mice. Collectively, these data show that NOX expression and activity are significantly upregulated with age in this humanized model of Aβ pathogenesis, and suggest that NOX-associated redox pathways are intimately linked to both the loss of cognitive function and the deposition of Aβ(1-42).

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In APP/PS1 mouse model of AD, the elevation of NOX activity is linked to cognitive impairment.
“In APP/PS1 mouse model of AD, the elevation of NOX activity is linked to cognitive impairment [47].”
From NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases (2021) · cites this paper as [47]

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“The earliest reports of cognitive deﬁcits are reported at 7 months in this model (Bruce-Keller et al., 2011).”
Background
NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases
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Background
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NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet
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Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow
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miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer’s Disease
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Cilostazol Suppresses Aβ-induced Neurotoxicity in SH-SY5Y Cells through Inhibition of Oxidative Stress and MAPK Signaling Pathway
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Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease
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Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice
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Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease
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NADPH oxidase 4 (NOX4) as a biomarker and therapeutic target in neurodegenerative diseases
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Huperzine A, reduces brain iron overload and alleviates cognitive deficit in mice exposed to chronic intermittent hypoxia
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Brain injury caused by HIV protease inhibitors: Role of lipodystrophy and insulin resistance
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The BET/BRD inhibitor JQ1 attenuates diabetes-induced cognitive impairment in rats by targeting Nox4-Nrf2 redox imbalance
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Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain
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Prolonged Diet Induced Obesity Has Minimal Effects Towards Cerebral Amyloid Angiopathy: Implications for Studying Obesity-Brain Interactions In Mice
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NADPH oxidase-derived production of reactive oxygen species is involved in learning and memory impairments in 16-month-old female rats
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The Role of NOX4 in Parkinson’s Disease with Dementia
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NADPH oxidase-dependent oxidative stress and mitochondrial damage in hippocampus of D-galactose-induced aging rats
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Mammalian Models in Alzheimer’s Research: An Update
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Effect of Selenium Treatment on Central Insulin Sensitivity: A Proteomic Analysis in β-Amyloid Precursor Protein/Presenilin-1 Transgenic Mice
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Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights From (Female) Mice and (Wo)men
Hunsberger, H. C., Lee, S., Jin, M., Lanio, M., Whye, A. R., Cha, J., Scarlata, M., Matthews, L. C., Jayaseelan, K., & Denny, C. A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.09.016 · Cited by 9 · see citing works
Neuroglia in neurodegeneration: Alzheimer, Parkinson, and Huntington disease
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Authors: Bruce-Keller, A. J., Gupta, S., Knight, A. G., Beckett, T. L., McMullen, J. M., Davis, P. R., Murphy, M. P., Van Eldik, L. J., St Clair, D., & Keller, J. N.
Affiliations: Pennington Biomedical Research Center (US)
University of Kentucky (US)
ORCID: Keller, Jeffrey N.
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2011-12
Volume: 44
Issue: 3
Pages: 317-326
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1016/j.nbd.2011.07.012
PMC: PMC3185143
OpenAlex: W1988205093
Cited by: 96
References: 98
Citations by year: 2026: 3 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 3 · 2018: 2 · 2017: 9 · 2016: 3 · 2015: 7 · 2014: 6 · 2013: 4 · 2012: 12
FWCI: 5.02
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
National Institute on Aging (P01AG005119, AG0 5119)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072476)
National Institute of Neurological Disorders and Stroke (NS46267, R01NS046267)
National Center for Research Resources (P20RR021945)
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, cognitive impairment, amyloid-beta 42, NADPH oxidase, NOX4, oxidative stress, humanized mice, amyloid deposition, synaptic proteins, aging, redox signaling
MeSH terms: Discs Large Homolog 1 Protein, Age Factors, Alzheimer Disease, Animals, Cognition Disorders, Disease Models, Animal, Gene Expression Regulation, Humans, Membrane Proteins, Mice, Transgenic, Peptide Fragments, Tubulin, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synapsins, NADPH Oxidases, Mice, Guanylate Kinases, Presenilin-1

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Cognitive impairment in humanized APP×PS1 mice is linked to Aβ1–42 and NOX activation

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