Amyloid Plaque Imaging with a Targeted MRI Contrast Agent in a Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Yongjie Xiong,1 Yi Qu,1 Zhe Min,1 Jun Wu,2 Suming Zhang,1 Zheng Xue1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, People’s Republic Of ChinaCorrespondence: Zheng Xue, Department of Neurology, Tongji Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China, Tel [phone], Email [email protected]: Magnetic resonance imaging (MRI) is a promising technique for detecting amyloid beta (Aβ) deposits in Alzheimer’s disease (AD). Contrast agents can reduce the scanning time and provide specific images to identify various structures. This study aimed to develop an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle coupled with a functional protein as a targeted MRI contrast agent to detect Aβ deposits.Methods: The targeted MRI contrast agent USPIO nanoparticle was coupled with Aβ(16– 20) (KLVFF) and HIV-1 trans-activating transcriptor-protein transduction domain (Tat-PTD) to produce the Tat-PTD-USPIO-Aβ(16– 20) structure to better penetrate the blood–brain barrier (BBB). In vitro studies were conducted to measure the coupling efficiency, including bicinchoninic acid protein assays, potassium ferrocyanide staining of cardiac microvascular endothelial cells, 1.5T MRI, and toxicity assessments. The contrast agent was injected into five transgenic mice and five age-matched wild-type mice for MRI and histological studies. The targeted agent was diluted, and all mice were scanned with a 7.0 Tesla MRI-scanner. The brain tissues were processed as frozen sections for Thioflavin-S staining to detect Aβ.Results: The coupling efficiency reached 97.75%. The developed MRI contrast agent successfully passed through biological membranes, bound to Aβ deposits, and decreased the MRI signal of tissue in vitro and in vivo. Compared with Aβ(16– 20) or Aβ(1– 40) alone, there was no significant toxicity of Tat-PTD or Aβ(16– 20) when coupled with USPIO nanoparticles.Conclusion: Our novel MRI contrast agent USPIO nanoparticle coupled with functional protein can pass through biological membranes in vitro and visualize Aβ deposits in AD animal models by MRI.Keywords: Alzheimer’s disease, transgenic mice, contrast agent, magnetic resonance imaging, nanomolecular imaging

Keywords

• alzheimer’s disease
• transgenic mice
• contrast agent
• magnetic resonance imaging
• nanomolecular imaging