California National Primate Research Center, University of California Davis, Davis, California, USA.
Center for Translational Research in Neurodegenerative Disease and Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
Alzheimers Dement. 2021 Jun;17(6):933-945. doi: 10.1002/alz.12318. Epub 2021 Mar 18.
Alzheimer's disease (AD) is a devastating condition with no effective treatments, with promising findings in rodents failing to translate into successful therapies for patients.
Targeting the vulnerable entorhinal cortex (ERC), rhesus monkeys received two injections of an adeno-associated virus expressing a double tau mutation (AAV-P301L/S320F) in the left hemisphere, and control AAV-green fluorescent protein in the right ERC. Noninjected aged-matched monkeys served as additional controls.
Within 3 months we observed evidence of misfolded tau propagation, similar to what is hypothesized to occur in humans. Viral delivery of human 4R-tau also coaptates monkey 3R-tau via permissive templating. Tau spreading is accompanied by robust neuroinflammatory response driven by TREM2+ microglia, with biomarkers of inflammation and neuronal loss in the cerebrospinal fluid and plasma.
These results highlight the initial stages of tau seeding and propagation in a primate model, a more powerful translational approach for the development of new therapies for AD.
阿尔茨海默病（AD）是一种毁灭性疾病，目前尚无有效的治疗方法，啮齿动物的有前景的研究结果未能转化为患者的成功治疗方法。
针对易受影响的内嗅皮层（ERC），恒河猴的左侧半球接受了两次表达双tau 突变（AAV-P301L/S320F）的腺相关病毒的注射，右侧 ERC 则接受了对照 AAV-绿色荧光蛋白的注射。未注射的年龄匹配的猴子作为额外的对照。
在 3 个月内，我们观察到错误折叠的 tau 传播的证据，类似于假设在人类中发生的情况。人类 4R-tau 的病毒传递也通过允许模板化与猴子 3R-tau 共结合。tau 的传播伴随着由 TREM2+小胶质细胞驱动的强烈神经炎症反应，脑脊液和血浆中的炎症和神经元丢失的生物标志物。
这些结果突出了在灵长类动物模型中 tau 播种和传播的初始阶段，这是一种更强大的转化方法，可用于开发 AD 的新疗法。
