Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide

Ateş, Şükrü; Ülger, Harun; Uçar, Sümeyye; Okan, Aslı; Ocak, Mert; Güvenilir, Ecma; Şükranlı, Zeynep Yılmaz; Kaymak, Emin; Doğanyiğit, Züleyha; Taheri, Serpil; Yilmaz, Seher

doi:10.3390/biom15040543

Open AccessArticle

Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide

by

Şükrü Ateş

^1,2

,

Harun Ülger

¹,

Sümeyye Uçar

¹

,

Aslı Okan

³,

Mert Ocak

⁴

,

Ecma Güvenilir

⁵,

Zeynep Yılmaz Şükranlı

⁵,

Emin Kaymak

³,

Züleyha Doğanyiğit

³,

Serpil Taheri

^5,6 and

Seher Yilmaz

^2,*

¹

Department of Anatomy, Faculty of Medicine, Erciyes University, Kayseri 38280, Turkey

²

Department of Anatomy, Faculty of Medicine, Yozgat Bozok University, Yozgat 66100, Turkey

³

Department of Histology and Embryology, Faculty of Medicine, Yozgat Bozok University, Yozgat 66100, Turkey

⁴

Department of Basic Medical Sciences, Anatomy, Faculty of Dentistry, Ankara University, Ankara 06100, Turkey

⁵

Betul Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri 38280, Turkey

⁶

Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri 38280, Turkey

^*

Author to whom correspondence should be addressed.

Biomolecules 2025, 15(4), 543; https://doi.org/10.3390/biom15040543

Submission received: 5 March 2025 / Revised: 29 March 2025 / Accepted: 2 April 2025 / Published: 7 April 2025

(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)

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Abstract

The onset of Alzheimer’s disease (AD) is attributed to widespread amyloid beta (Aβ) plaque accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. However, the underlying mechanism of AD remains unclear, and no curative treatment currently exists. The aim was to investigate the effect of thymoquinone by suppressing the RAGE/NOX4 pathway in AD. Mice (n = 60) were divided into five groups, and an experimental AD model induced by an Aβ_1–42 peptide was established in two groups. We also administered 5 mg/kg thymoquinone (TMQ) to the mice for its properties to slow or treat neurodegeneration in AD. Behavioral tests for memory and emotional states, micro-computed tomography (Micro CT) to assess brain volume, ELISA to measure malondialdehyde (MDA) levels, hematoxylin and eosin staining (H&E) to evaluate neuronal degeneration were used. Immunohistochemical (IHC), Western blot (WB), and real-time polymerase chain reaction (PCR) methods were used to evaluate the inhibitory effect of TMQ on a receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) signaling in AD. The results showed that TMQ may have ameliorative effects on memory, spatial learning, learning ability, and anxiety in AD. We showed that TMQ has an antioxidative effect by decreasing MDA levels by the ELSIA method (p < 0.05). There was a marked increase in neuronal degeneration in AD mice compared to other groups (p < 0.05). We concluded that TMQ could ameliorate neuronal degeneration in AD by H&E staining and suppress RAGE/NOX4 signaling by IHC and WB analysis. We concluded that TMQ could be therapeutic in AD by reducing AB expression level by IHC analysis (p < 0.05). Real-time PCR analysis showed that APP (p < 0.05), RAGE, and NOX4 (p < 0.05) gene expressions could be reduced by TMQ. In conclusion, TMQ has a high therapeutic potential in AD and an effective preventive and therapeutic strategy can be developed with more comprehensive studies on TMQ.

Keywords: Alzheimer’s disease; thymoquinone; RAGE; NOX4; brain anatomy; micro CT

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MDPI and ACS Style

Ateş, Ş.; Ülger, H.; Uçar, S.; Okan, A.; Ocak, M.; Güvenilir, E.; Şükranlı, Z.Y.; Kaymak, E.; Doğanyiğit, Z.; Taheri, S.; et al. Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide. Biomolecules 2025, 15, 543. https://doi.org/10.3390/biom15040543

AMA Style

Ateş Ş, Ülger H, Uçar S, Okan A, Ocak M, Güvenilir E, Şükranlı ZY, Kaymak E, Doğanyiğit Z, Taheri S, et al. Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide. Biomolecules. 2025; 15(4):543. https://doi.org/10.3390/biom15040543

Chicago/Turabian Style

Ateş, Şükrü, Harun Ülger, Sümeyye Uçar, Aslı Okan, Mert Ocak, Ecma Güvenilir, Zeynep Yılmaz Şükranlı, Emin Kaymak, Züleyha Doğanyiğit, Serpil Taheri, and et al. 2025. "Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide" Biomolecules 15, no. 4: 543. https://doi.org/10.3390/biom15040543

APA Style

Ateş, Ş., Ülger, H., Uçar, S., Okan, A., Ocak, M., Güvenilir, E., Şükranlı, Z. Y., Kaymak, E., Doğanyiğit, Z., Taheri, S., & Yilmaz, S. (2025). Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide. Biomolecules, 15(4), 543. https://doi.org/10.3390/biom15040543

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Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide

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