Characterization of Cerebral Damage in a Monkey Model of Alzheimer’s Disease Induced by Intracerebroventricular Injection of Streptozotocin

Article type: Research Article

Authors: Yeo, Hyeon-Gu^{a; b; 1} | Lee, Youngjeon^{a; 1} | Jeon, Chang-Yeop^{a; c; 1} | Jeong, Kang-Jin^a | Jin, Yeung Bae^a | Kang, Philyong^a | Kim, Sun-Uk^a | Kim, Ji-Su^a | Huh, Jae-Won^a | Kim, Young-Hyun^a | Sim, Bo-Woong^a | Song, Bong-Seok^a | Park, Young-Ho^a | Hong, Yonggeun^d | Lee, Sang-Rae^{a; *} | Chang, Kyu-Tae^{a; b; *}

Affiliations: [a] National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea | [b] Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea | [c] Department of Biomedical Engineering, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea | [d] Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Republic of Korea

Correspondence: [*] Correspondence to: Kyu-Tae Chang, PhD, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Chungwon-gun, Chungbuk 363-883, Republic of Korea. Tel.: +82 43 240 6300; Fax: +82 43 240 6309; E-mail: [email protected]

Correspondence: [*] Correspondence to: Sang-Rae Lee, DVM, PhD, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea.Tel.: +82 43 240 6322; Fax: +82 43 240 6309; [email protected]

Note: [1] These authors contributed equally to this work.

Abstract: In line with recent findings showing Alzheimer’s disease (AD) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-STZ) administration has been proposed as a representative experimental model of AD. Although icv-STZ rodent models of AD have been increasingly researched, studies in non-human primate models are very limited. In this study, we aimed to characterize the cerebral damage caused by icv-STZ in non-human primates; to achieve this, three cynomolgus monkeys (Macaca fascicularis) were administered four dosages of STZ (2 mg/kg) dissolved in artificial cerebrospinal fluid and another three controls were injected with only artificial cerebrospinal fluid at the cerebellomedullary cistern. In vivo neuroimaging was performed with clinical 3.0 T MRI, followed by quantitative analysis with FSL for evaluation of structural changes of the brain. Immunohistochemistry was performed to evaluate cerebral histopathology. We showed that icv-STZ caused severe ventricular enlargement and parenchymal atrophy, accompanying amyloid-β deposition, hippocampal cell loss, tauopathy, ependymal cell loss, astrogliosis, and microglial activation, which are observed in human aged or AD brain. The findings suggest that the icv-STZ monkey model would be a valuable resource to study the mechanisms and consequences of a variety of cerebral pathologies including major pathological hallmarks of AD. Furthermore, the study of icv-STZ monkeys could contribute to the development of treatments for age- or AD-associated cerebral changes.

Keywords: Alzheimer’s disease, animal model, brain, monkey, streptozotocin

DOI: 10.3233/JAD-143222

Journal: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 989-1005, 2015