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Theranostics 2020; 10(25):11794-11819. doi:10.7150/thno.44152 This issue Cite

Research Paper

Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease

Yuanyuan Shen¹, Lingchen Hua¹, Chih-Kuang Yeh³, Liming Shen⁴, Ming Ying⁴, Zaijun Zhang⁵, Gongping Liu⁶, Shupeng Li⁷, Siping Chen¹, Xin Chen^1✉, Xifei Yang^2✉

1. National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
2. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.
3. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013 Taiwan.
4. College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, China.
5. Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, College of Pharmacy, Jinan University Guangzhou, 510632, China.
6. Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
7. State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

✉ Corresponding authors: Xin Chen & Xifei Yang; Dr. Xifei Yang, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen, 518055, People's Republic of China. Tel: +86 75525601914, Fax: +86 755 25508584, E-mail: xifeiyangcom; Dr. Xin Chen, School of Biomedical Engineering, Xili Campus of Shenzhen University, 1066 Xueyuan Avenue, Nanshan District, Shenzhen, 518071, People's Republic of China. Tel: +86 755 86671921, Fax: +86 755 26910441, E-mail: chenxinedu.cn. More

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far.

Methods: In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-β (Aβ) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of Aβ and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of Aβ deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry.

Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal Aβ, extracellular diffuse Aβ deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both Aβ deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing Aβ deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3×Tg-AD mice.

Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both Aβ and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications.

Keywords: Triple transgenic mouse model of Alzheimer's disease, blood-brain barrier, focused ultrasound, microbubbles, behavioral tests

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