A nonhuman primate model with Alzheimer′s disease-like pathology induced by hippocampal overexpression of human tau

被引：6

作者：

Jiang, Zhouquan ^{[1
]}

Wang, Jing ^{[2
]}

Qin, Yongpeng ^{[1
]}

Liu, Shanggong ^{[1
]}

Luo, Bin ^{[1
]}

Bai, Fan ^{[1
]}

Wei, Huiyi ^{[3
,4
]}

Zhang, Shaojuan ^{[3
,4
]}

Wei, Junjie ^{[3
,4
]}

Ding, Guoyu ^{[1
]}

Ma, Long ^{[1
]}

He, Shu ^{[1
]}

Chen, Rongjie ^{[1
]}

Sun, Ying ^{[1
]}

Chen, Yi ^{[1
]}

Wang, Lu ^{[3
,4
]}

Xu, Hao ^{[3
,4
]}

Wang, Xiangyu ^{[2
]}

Chen, Gong ^{[1
]}

Lei, Wenliang ^{[1
]}

机构：

[1] Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Guangzhou 510630, Guangdong, Peoples R China

[2] Jinan Univ, Affiliated Hosp 1, Dept Neurosurg, Guangzhou 510630, Guangdong, Peoples R China

[3] Jinan Univ, Affiliated Hosp 1, PET CT MRI Ctr, Guangzhou 510630, Guangdong, Peoples R China

[4] Jinan Univ, Dept Nucl Med, Guangzhou 510630, Guangdong, Peoples R China

来源：

ALZHEIMERS RESEARCH & THERAPY | 2024年 / 16卷 / 01期

关键词：

Alzheimer ' s disease; Human tau; 3R tau; 4R tau; Tau hyperphosphorylation; Nonhuman primate; Neuroinflammation; Blood vessel damage; Cognitive decline; MILD COGNITIVE IMPAIRMENT; POSITRON-EMISSION-TOMOGRAPHY; AMYLOID-BETA DEPOSITS; MOUSE MODEL; ASTROCYTE ACTIVATION; VASCULAR DISORDER; ENTORHINAL CORTEX; CEREBRAL-CORTEX; NEURONAL LOSS; MICROGLIA;

D O I：

10.1186/s13195-024-01392-0

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background Alzheimer ' s disease (AD) is one of the most burdening diseases of the century with no disease-modifying treatment at this time. Nonhuman primates (NHPs) share genetic, anatomical, and physiological similarities with humans, making them ideal model animals for investigating the pathogenesis of AD and potential therapies. However, the use of NHPs in AD research has been hindered by the paucity of AD monkey models due to their long generation time, ethical considerations, and technical challenges in genetically modifying monkeys. Methods Here, we developed an AD-like NHP model by overexpressing human tau in the bilateral hippocampi of adult rhesus macaque monkeys. We evaluated the pathological features of these monkeys with immunostaining, Nissl staining, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), positron emission tomography (PET), and behavioural tests. Results We demonstrated that after hippocampal overexpression of tau protein, these monkeys displayed multiple pathological features of AD, including 3-repeat (3R)/4-repeat (4R) tau accumulation, tau hyperphosphorylation, tau propagation, neuronal loss, hippocampal atrophy, neuroinflammation, A beta clearance deficits, blood vessel damage, and cognitive decline. More interestingly, the accumulation of both 3R and 4R tau is specific to NHPs but not found in adult rodents. Conclusions This work establishes a tau-induced AD-like NHP model with many key pathological and behavioural features of AD. In addition, our model may potentially become one of the AD NHP models adopted by researchers worldwide since it can be generated within 2 similar to 3 months through a single injection of AAVs into the monkey brains. Hence, our model NHPs may facilitate mechanistic studies and therapeutic treatments for AD.

引用

页数：24

共 117 条

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