Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding

基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证

• 批准号: 10668407
• 负责人: Afonso C Silva
• 金额: $ 110.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668407
• 关键词: Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Animal Model; Behavior; Behavioral; Biological Markers; Biopsy; Blood - brain barrier anatomy; Brain; Callithrix; Callithrix jacchus jacchus; Cell Culture Techniques; Cell Death; Cerebrovascular Circulation; Clinical; Clinical Data; Clinical assessments; Cognitive; Data; Dementia; Development; Disease Progression; Evaluation; Female; Fibroblasts; Future; Genetic; Genetic Variation; Goals; Hippocampus; Human; Image; Impaired cognition; Impairment; In Vitro; Injections; Late Onset Alzheimer Disease; Light; MAPT gene; Magnetic Resonance Imaging; Maps; Measures; Memory Loss; Metabolism; Modeling; Motor; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathology; Persons; Phenotype; Plasma; Positron-Emission Tomography; Protein Fragment; Recombinant adeno-associated virus (rAAV); Rodent Model; Senile Plaques; Sensory; Serotyping; Severities; Skin; Staging; Symptoms; Testing; Time; Transfection; Translational Research; Validation; Work; aged; aging brain; behavior test; blood-brain barrier crossing; clinical biomarkers; cognitive process; cognitive testing; cohort; comparative efficacy; cytokine; efficacy evaluation; entorhinal cortex; experimental study; extracellular; hyperphosphorylated tau; improved; in vivo evaluation; intravenous administration; male; nerve stem cell; neurofibrillary tangle formation; neurofilament; neuropathology; nonhuman primate; novel therapeutics; social; spatiotemporal; tau Proteins; tau aggregation; transcriptomics; translational potential; translational study

PROJECT TITLE: Development and Validation of a Marmoset Model of Late-Onset Alzheimer’s Disease Based on Tau Seeding PROJECT SUMMARY/ABSTRACT: Alzheimer’s disease (AD), the most common cause of dementia, currently afflicts 5.8 million Americans. By 2050, the number of people with AD could reach nearly 14 million. Histopathologically, AD is characterized by the formation of extracellular aggregates (plaques) of beta-amyloid (Aβ) protein fragments and intracellular aggregates (neurofibrillary tangles, NFTs) of a hyperphosphorylated form of the microtubule-associated protein tau (MAPT). Increasing evidence indicates that both Aβ plaques and NFTs begin to accumulate in the brain decades before symptoms emerge. The long delay between Aβ and tau manifestation and the onset of memory loss and cognitive decline in AD makes it difficult to properly model AD using short-lived animal models, such as mice. As age and genetic variation are two of the most significant risk factors for AD, there is a critical need to develop improved animal models of AD that incorporate genetic variability, aging, and higher- order cognitive processes that better align with humans. The common marmoset (Callithrix jacchus) is a small non-human primate (NHP) ideally poised to fill this need. They display social and cognitive behaviors that are more similar to those of humans. Marmosets live on average 12-13 years and are considered aged at eight years. Aβ plaques and hyperphosphorylated tau occur naturally in the brain of aging marmosets. Developing strategies to accelerate the onset of cognitive decline related to the presence of pathological hallmarks of AD in marmosets would lead to establishing an NHP model with improved translational potential relative to rodent models. The overall goal of this proposal is to develop and validate an induced marmoset model of late-onset AD. Converging clinical data indicates that the severity of cognitive impairment in sporadic AD correlates best with the burden of NFTs. We hypothesize that injecting the brain of aging marmosets with tau will seed the formation and propagation of NFTs and accelerate the emergence of impairments in a spectrum of AD-related sensory, motor, cognitive and non-cognitive phenotypes associated with disease progression. We will test this hypothesis in two aims. In Aim 1, we will use neuronal cell cultures derived from aging marmosets to quantify the spontaneous presence of AD-related pathology in vitro and evaluate the efficacy of tau seeding strategies in accelerating the development of NFTs and promoting neurodegeneration and cell death. In Aim 2, we will seed the brains of aging marmosets with tau, and perform a comprehensive longitudinal evaluation of functional, behavioral, and clinical biomarkers of AD in the tau-seeded marmosets. This work will lead to the establishment of a validated NHP model of late-onset AD that will be invaluable in translational research to elucidate the pathogenic mechanisms of AD and contribute to developing new therapeutics for AD.

项目名称:

项目成果

An integrated resource for functional and structural connectivity of the marmoset brain.

• DOI: 10.1038/s41467-022-35197-2
• 发表时间: 2022-12-01
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Tian, Xiaoguang;Chen, Yuyan;Majka, Piotr;Szczupak, Diego;Perl, Yonatan Sanz;Yen, Cecil Chern-Chyi;Tong, Chuanjun;Feng, Furui;Jiang, Haiteng;Glen, Daniel;Deco, Gustavo;Rosa, Marcello G. P.;Silva, Afonso C.;Liang, Zhifeng;Liu, Cirong
• 通讯作者: Liu, Cirong

The relevance of heterotopic callosal fibers to interhemispheric connectivity of the mammalian brain.

• DOI: 10.1093/cercor/bhac377
• 发表时间: 2022-09
• 期刊: Cerebral cortex
• 影响因子: 3.7
• 作者: Diego Szczupak;Pamela Meneses Iack;Danielle Rayêe;Cirong Liu;R. Lent;F. Tovar-Moll;Afonso C. Silva

Direct interhemispheric cortical communication via thalamic commissures: a new white-matter pathway in the primate brain.

通过丘脑连合的直接半球间皮质通讯：灵长类动物大脑中的新白质通路。

• DOI: 10.1101/2023.06.15.545128
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Szczupak,Diego;Schaeffer,DavidJ;Tian,Xiaoguang;Choi,Sang-Ho;Fang-Cheng;Iack,PamelaMeneses;Campos,ViniciusP;Mayo,JPatrick;Patsch,Janina;Mitter,Christian;Haboosheh,Amit;Vieira,MarceloAC;Kasprian,Gregor;Tovar-Moll,Fernanda;Le
• 通讯作者: Le

An open access resource for functional brain connectivity from fully awake marmosets.

• DOI: 10.1016/j.neuroimage.2022.119030
• 发表时间: 2022-05-15
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Schaeffer, David J.;Klassen, L. Martyn;Hori, Yuki;Tian, Xiaoguang;Szczupak, Diego;Yen, Cecil Chern-Chyi;Clery, Justine C.;Gilbert, Kyle M.;Gati, Joseph S.;Menon, Ravi S.;Liu, CiRong;Everling, Stefan;Silva, Afonso C.
• 通讯作者: Silva, Afonso C.

Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease.

• DOI: 10.1002/trc2.12417
• 发表时间: 2023-07
• 期刊: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
• 影响因子: 4.8
• 作者: Sukoff Rizzo, Stacey J;Homanics, Gregg;Schaeffer, David J;Schaeffer, Lauren;Park, Jung Eun;Oluoch, Julia;Zhang, Tingting;Haber, Annat;Seyfried, Nicholas T;Paten, Benedict;Greenwood, Anna;Murai, Takeshi;Choi, Sang Ho;Huhe, Hasi;Kofler, Julia;Strick, Peter L;Carter, Gregory W;Silva, Afonso C
• 通讯作者: Silva, Afonso C