Repeated Intra-cisterna Magna Injections with Amyloid-beta Oligomers to Induce Alzheimer's Disease in Cynomolgus Monkey (Macaca fascicularis): A Pilot Study

초록

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which results in cognitive decline and memory loss, characterized by the accumulation of amyloid beta (A(3) plaques and neurofibrillary tangles in the brain. Despite numerous efforts to develop animal models of AD across various species to understand its pathological characteristics and underlying mechanisms, the model that accurately mimics the pathological phenotypes of AD remains elusive. In this study, we aimed to induce sporadic AD pathological progression in non-human primates (NHP) through the repeated administration of A(3 oligomers (A(3O) via the CBCT-guided intra-cisterna manga (ICM) injection. Cynomolgus monkeys were administered A(3O twice a week for four weeks, and then euthanized one week after the final injection. We found that A(3O-injected NHP developed AD pathologies, including A(3 deposition, synaptic impairment, and neuroinflammation in the CA1 area of the hippocampus. Additionally, the levels of hyperphosphorylated tau were significantly increased in the cerebrospinal fluid (CSF) of A(3O-injected NHP. Our results demonstrate that repeated A(3O injection via the ICM route induces several early-stage AD-like neuropathological alterations, including intracellular A(3 accumulation, tau phosphorylation, and synaptic dysfunction. The present study indicates that repeated ICM administration of A(3O could be good approach to reproduce a translational NHP model of AD, enabling the study of AD pathogenesis and pre-clinical testing of potential therapeutic candidates for AD.

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