Bis(ethylmaltolato)oxidovanadium(iv) inhibited the pathogenesis of Alzheimer’s disease in triple transgenic model mice

Author:

He Zhijun1,Han Shuangxue2,Wu Chong1,Liu Lina34,Zhu Huazhang1,Liu Ang34,Lu Qiying1,Huang Jingqiang1,Du Xiubo1,Li Nan1,Xie Qinguo2,Wan Lu2,Ni Jiazuan1,Chen Lingling34,Yang Xiaogai5,Liu Qiong1ORCID

Affiliation:

1. Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, 518060 Shenzhen, China. Fax: +86 75586713951; Tel: +86 75526535432

2. College of Life Science, Huazhong University of Science & Technology, Wuhan 430073, China

3. College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, 518118, China. Fax: +86 75526911505; Tel: +86 75526911505

4. College of Optoelectronics Engineering, Shenzhen University, 518060 Shenzhen, China

5. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Tel: +86-010-82805956

Abstract

Abstract Vanadium compounds have been reported to mimic the anti-diabetes effects of insulin on rodent models, but their effects on Alzheimer’s disease (AD) have rarely been explored. In this paper, 9-month-old triple transgenic AD model mice (3×Tg-AD) received bis(ethylmaltolato)oxidovanadium(iv) (BEOV) at doses of 0.2 mmol L−1 (68.4 μg mL−1) and 1.0 mmol L−1 (342 μg mL−1) for 3 months. BEOV at both doses was found to improve contextual memory and spatial learning in AD mice. It also improved glucose metabolism and protected neuronal synapses in the AD brain, as evidenced respectively by 18F-labeled fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) scanning and by transmission electron microscopy. Inhibitory effects of BEOV on β-amyloid (Aβ) plaques and neuronal impairment in the cortex and hippocampus of fluorescent AD mice were visualized three-dimensionally by applying optical clearing technology to brain slices before confocal laser scanning microscopy. Western blot analysis semi-quantitatively revealed the altered levels of Aβ42 in the brains of wildtype, AD, and AD treated with 0.2 and 1.0 mmol L−1 BEOV mice (70.3%, 100%, 83.2% and 56.8% in the hippocampus; 82.4%, 100%, 66.9% and 42% in the cortex, respectively). The mechanism study showed that BEOV increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) (140%, 100%, 142% and 160% in the hippocampus; 167%, 100%, 124% and 133% in the cortex) to inactivate the JAK2/STAT3/SOCS-1 pathway and to block the amyloidogenesis cascade, thus attenuating Aβ-induced insulin resistance in AD models. BEOV also reduced protein tyrosine phosphatase 1B (PTP1B) expression (74.8%, 100%, 76.5% and 53.8% in the hippocampus; 71.8%, 100%, 94.2% and 81.8% in cortex) to promote insulin sensitivity and to stimulate the PI3K/Akt/GSK3β pathway, subsequently reducing tau hyperphosphorylation (phosphorylated tau396 levels were 51.1%, 100%, 56.1% and 50.2% in the hippocampus; 22.2%, 100%, 36.1%, and 24% in the cortex). Our results suggested that BEOV reduced the pathological hallmarks of AD by targeting the pathways of PPARγ and PTP1B in 3×Tg AD mice.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Metals and Alloys,Biochemistry,Biomaterials,Biophysics,Chemistry (miscellaneous)

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