BioRxiv. 2022 Oct 30
Zhouquan Jiang, Jing Wang, Bin Luo, Fan Bai, Yongpeng Qin, Huiyi Wei, Shaojuan Zhang, Junjie Wei, Guoyu Ding, Long Ma, Shu He, Rongjie Chen, Lu Wang, Hao Xu, Xiangyu Wang, Gong Chen, Wenliang Lei
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Research Field: CNS

Keywords: Alzheimer’s disease, human tau, non-human primate, neuroinflammation, blood vessel damage, cognitive decline

Dose: 7.5ul AAVs (10^11~12 GC/ml, flow rate: 800 nl/min) were injected into each injection site

Routes of Administration: stereotaxic injection

Targeted organ: brain

Animal or cell line strain: monkey

Abstract

Alzheimer’s disease (AD) is one of the most burdening diseases of the century with no disease-modifying treatment yet. Non-human primates (NHPs) share genetic, anatomical and physiological similarities with humans, making them an ideal model for investigating the pathogenesis and therapeutics of AD. However, the applications of NHPs in AD research have been hindered by the paucity of spontaneous or induced monkey models for AD due to their long generation time, ethical considerations and technical challenges in making genetically modified monkeys. Here we developed an AD-like NHP model by overexpressing human tau in bilateral hippocampi of adult rhesus macaque monkeys. We evaluated the pathological features of these monkeys with immunostaining, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and behavioral tests. We demonstrated that after hippocampal overexpression of human tau, the rhesus macaque monkeys displayed multiple pathological features of AD, including neurofibrillary tangle formation, neuronal loss, hippocampal atrophy, neuroinflammation, Aβ clearance deficit, blood vessel damage and cognitive decline. This work establishes a human tau-induced AD-like NHP model that may facilitate mechanistic studies and therapeutic treatments for AD.

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