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ORIGINAL RESEARCH article
Front. Physiol.
Sec. Integrative Physiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1529981
Compensatory Enhancement of Orexinergic System Functionality Induced by Amyloid-β Protein: A Neuroprotective Response in Alzheimer's Disease
Provisionally accepted- 1 Medical College, Yangzhou University, Yangzhou, China
- 2 The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, China
- 3 Department of Basic Medical Sciences, Guizhou University of Chinese Medicine, Guiyang, China
- 4 Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou, China
Background: Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management. Methods: This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ₁₋₄₂ oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes. Results: Injection of Aβ₁₋₄₂ oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons. Conclusions: Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function. Commented [CZ1]: Added relevant references to support the statement on AD incidence, prevalence, and mortality rates. Commented [CZ9]: The existing c-Fos immunohistochemistry image has been magnified to enhance its visibility and clarity. Commented [CZ8]: Dex group image (non-surgical) has been added.
Keywords: Alzheimer's disease, Orexin (hypocretin), amyloid-β protein, cognitive impairment, Neuroprotection
Received: 18 Nov 2024; Accepted: 05 Mar 2025.
Copyright: © 2025 Zhuang, Yan, Lu, Zhou, Liu, Shi and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yan Li, Medical College, Yangzhou University, Yangzhou, China
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