A nonhuman primate model with Alzheimer's disease-like pathology induced by hippocampal overexpression of human tau.
A nonhuman primate model with Alzheimer's disease-like pathology induced by hippocampal overexpression of human tau.
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DOI：
10.1186/s13195-024-01392-0
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发表时间：
2024-01-27
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影响因子：
--
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阿尔茨海默病（AD）是世纪最严重的疾病之一，目前尚无改善疾病的治疗方法。非人灵长类动物（NHP）与人类有着遗传、解剖和生理上的相似性，使其成为研究AD发病机制和潜在治疗方法的理想模型动物。然而，NHP在AD研究中的使用受到AD猴模型缺乏的阻碍，这是由于它们的世代时间长，伦理考虑和转基因猴的技术挑战。在这里，我们开发了一个AD样NHP模型过表达人类tau蛋白在成年恒河猴的双侧前额叶。我们评估了这些猴子的病理特征，免疫染色，尼氏染色，脑脊液（CSF）分析，磁共振成像（MRI），正电子发射断层扫描（PET），和行为测试。我们证明，在海马过度表达tau蛋白后，这些猴表现出AD的多种病理学特征，包括3-重复（3R）/4-重复（4 R）tau积聚、tau过度磷酸化、tau增殖、神经元丢失、海马萎缩、神经炎症、Aβ清除缺陷、血管损伤和认知能力下降。更有趣的是，3R和4 R tau的积累对NHP是特异性的，但在成年啮齿动物中没有发现。本工作建立了tau诱导的AD样NHP模型，具有AD的许多关键病理和行为特征。此外，我们的模型有可能成为全球研究人员采用的AD NHP模型之一，因为它可以在2 ~ 3个月内通过单次注射AAV到猴脑中产生。因此，我们的模型NHP可能有助于AD的机制研究和治疗。在线版本包含补充材料，可通过10.1186/s13195-024-01392-0获得。
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. 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. 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, Aβ 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. 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 ~ 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. The online version contains supplementary material available at 10.1186/s13195-024-01392-0.
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DOI：
10.1002/alz.12318
发表时间：
2021-06
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
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作者：
Beckman D;Chakrabarty P;Ott S;Dao A;Zhou E;Janssen WG;Donis-Cox K;Muller S;Kordower JH;Morrison JH
通讯作者：
Morrison JH
影响因子：
12.7
作者：
Ashton NJ;Pascoal TA;Karikari TK;Benedet AL;Lantero-Rodriguez J;Brinkmalm G;Snellman A;Schöll M;Troakes C;Hye A;Gauthier S;Vanmechelen E;Zetterberg H;Rosa-Neto P;Blennow K
通讯作者：
Blennow K
DOI：
10.1002/alz.12325
发表时间：
2021-06
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Datta D;Leslie SN;Wang M;Morozov YM;Yang S;Mentone S;Zeiss C;Duque A;Rakic P;Horvath TL;van Dyck CH;Nairn AC;Arnsten AFT
通讯作者：
Arnsten AFT
影响因子：
4.3
作者：
Buchman AS;Bennett DA
通讯作者：
Bennett DA
影响因子：
4.6
作者：
Criscuolo C;Fontebasso V;Middei S;Stazi M;Ammassari-Teule M;Yan SS;Origlia N
通讯作者：
Origlia N