Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.
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DOI：
10.1186/s13024-022-00547-7
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发表时间：
2022-06-11
影响因子：
15.1
通讯作者：
Sanchez, Pascal E.
中科院分区：
文献类型：
--
作者：
Xia, Dan;Lianoglou, Steve;Sandmann, Thomas;Calvert, Meredith;Suh, Jung H.;Thomsen, Elliot;Dugas, Jason;Pizzo, Michelle E.;DeVos, Sarah L.;Earr, Timothy K.;Lin, Chia-Ching;Davis, Sonnet;Ha, Connie;Leung, Amy Wing-Sze;Hoang Nguyen;Chau, Roni;Yulyaningsih, Ernie;Lopez, Isabel;Solanoy, Hilda;Masoud, Shababa T.;Liang, Chun-chi;Lin, Karin;Astarita, Giuseppe;Khoury, Nathalie;Zuchero, Joy Yu;Thorne, Robert G.;Shen, Kevin;Miller, Stephanie;Palop, Jorge J.;Garceau, Dylan;Sasner, Michael;Whitesell, Jennifer D.;Harris, Julie A.;Hummel, Selina;Gnorich, Johannes;Wind, Karin;Kunze, Lea;Zatcepin, Artem;Brendel, Matthias;Willem, Michael;Haass, Christian;Barnett, Daniel;Zimmer, Till S.;Orr, Anna G.;Scearce-Levie, Kimberly;Lewcock, Joseph W.;Di Paolo, Gilbert;Sanchez, Pascal E.
关键词：
几十年前就发现了家族性阿尔茨海默病（AD）的基因突变，但该领域仍在为患者寻找变革性疗法。虽然基于突变转基因过表达的小鼠模型已经在疾病机制方面产生了关键的见解，但这些模型受到人为因素的影响，包括转基因的随机遗传整合、异位表达和非生理蛋白水平。使用基因敲入方法的新型小鼠模型的基因工程解决了其中的一些限制。随着越来越多的证据表明小胶质细胞在AD中所起的作用，在这些模型中对表型小胶质细胞的高维方法对于完善我们对大脑中免疫反应的理解至关重要。我们设计了一种新的App敲入小鼠模型（AppSAA），使用同源重组将三种致病编码突变（瑞典，北极和奥地利）引入小鼠App基因。在不同年龄的杂合和纯合AppSAA小鼠中，在脑和/或生物流体中表征β淀粉样蛋白病理学、神经变性、神经胶质反应、脑代谢和行为表型。将野生型同窝小鼠用作实验对照。我们使用原位成像技术来确定淀粉样斑块的全脑分布，并将其与其他AD小鼠模型和人脑病理学进行比较。为了进一步探索小胶质细胞对AD相关病理学的反应，我们从脑中分离具有纤维状Aβ含量的小胶质细胞，并进行转录组学和代谢组学分析以及体内脑成像以测量能量代谢和小胶质细胞反应。最后，我们还在各种行为测定中表征了小鼠。利用多组学方法，我们发现了多种脂质和代谢物的深刻改变，以及具有高细胞内Aβ含量的小胶质细胞中疾病相关转录组反应的加剧。AppSAA基因敲入小鼠模型重现了AD的关键病理学特征，例如实质淀粉样蛋白斑块和血管淀粉样蛋白沉积物的进行性积累、星形胶质细胞和小胶质细胞反应改变以及神经变性的CSF标志物升高。这些观察结果与TSPO和FDG-PET脑信号增加以及随着动物年龄增长的多动表型相关。我们的研究结果表明，小胶质细胞中的纤维状Aβ与脂质稳态异常相关，与溶酶体功能障碍和泡沫细胞表型以及深刻的免疫代谢紊乱一致，为进一步研究小胶质细胞中对AD相关发病机制的代谢途径开辟了新的途径。在这种新颖的开放式小鼠模型中，AD病理特征的深入表征应该成为科学界研究疾病相关生物学的资源。在线版本包含补充材料，可通过10.1186/s13024-022-00547-7获得。
Genetic mutations underlying familial Alzheimer’s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. We engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays. Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged. Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology. The online version contains supplementary material available at 10.1186/s13024-022-00547-7.
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影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
23.9
作者：
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通讯作者：
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作者：
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影响因子：
82.9
作者：
HAASS, C;LEMERE, CA;SELKOE, DJ
通讯作者：
SELKOE, DJ
影响因子：
5.3
作者：
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通讯作者：
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