Neuroprotective effects of vitamin D in an Alzheimer's disease rat model: Improvement of mitochondrial dysfunction via calcium/calmodulin-dependent protein kinase kinase 2 activation of Sirtuin1 phosphorylation

IF 5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2023-10-06 DOI:10.1002/biof.2013

Marwa Mohanad, Shimaa K. Mohamed, Basma E. Aboulhoda, Maha A. E. Ahmed

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Abstract

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl₃ + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl₃ + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca²⁺ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aβ), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aβ aggregation, and elevated p-Tau levels in the AlCl₃ + D-gal-induced AD rat model. In AlCl₃ + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca²⁺ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl₃ + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation.

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维生素D在阿尔茨海默病大鼠模型中的神经保护作用：通过钙/钙调蛋白依赖性蛋白激酶2激活Sirtuin1磷酸化改善线粒体功能障碍。

线粒体功能障碍是阿尔茨海默病（AD）发病机制的早期事件。为了评估维生素D3（Vit.D）对神经发生的影响，我们在氯化铝-D-半乳糖（AlCl3-D-gal）诱导的AD大鼠模型中，通过钙/钙调蛋白依赖性蛋白激酶2（CAMKK2）介导的SIRT1磷酸化，研究了维生素D3在减轻认知障碍和线粒体功能障碍中的作用。大鼠分为四组：对照组、AlCl3组 + D-加仑（10 + 60 mg/kg，ip），维生素D（500 IU/kg，po）和AlCl3 + 采用新型物体识别（NOR）、Morris水迷宫和被动回避（PA）测试来测量记忆能力。海马组织通过定量实时聚合酶链式反应（qRT-PCR）、CAMKK2、p-SIRT1、磷酸化AMP活化蛋白激酶（p-AMPK）、动态相关蛋白-1（Drp1）和线粒体融合蛋白-1（Mnf1）蛋白，通过蛋白质印迹和Ca2+水平评估维生素D3受体（VDR）和过氧化物酶体增殖物激活受体-γ-共激活因子-1α（PGC-1α）的表达，内皮一氧化氮合酶（eNOS）、超氧化物歧化酶（SOD）、淀粉样蛋白β（Aβ）和磷酸化tau（p-tau）。维生素D引起的海马损伤逆转了认知能力下降和Aβ聚集，并升高了AlCl3中的p-Tau水平 + D-半乳糖诱导的AD大鼠模型。在AlCl3中 + D-半乳糖暴露大鼠，维生素D诱导VDR表达，使Ca2+水平正常化，升高CAMKK2、p-AMPK、p-SIRT1和PGC-1α表达。维生素D降低了Drp1，诱导了Mnf1，增加了线粒体膜电位，保留了线粒体结构，恢复了正常的线粒体功能，并在AlCl3中保持了正常的eNOS水平和SOD活性 + D-gal大鼠。总之，我们的研究结果证明维生素D可以改善AlCl3的认知缺陷 + D-半乳糖通过CAMKK2-AMPK/SIRT1通路上调恢复正常线粒体功能和减少炎症和氧化应激诱导AD。

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来源期刊

BioFactors 生物-内分泌学与代谢

CiteScore

11.50

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.