Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.
Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.
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小胶质细胞的缺乏促进了阿尔茨海默氏病小鼠的多种病理和早期致死性。
DOI：
10.1016/j.celrep.2022.110961
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发表时间：
2022-06-14
期刊：
影响因子：
8.8
通讯作者：
Blurton-Jones, Mathew
中科院分区：
文献类型：
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作者：
Shabestari, Sepideh Kiani;Morabito, Samuel;Danhash, Emma Pascal;McQuade, Amanda;Sanchez, Jessica Ramirez;Miyoshi, Emily;Chadarevian, Jean Paul;Claes, Christel;Coburn, Morgan Alexandra;Hasselmann, Jonathan;Hidalgo, Jorge;Tran, Kayla Nhi;Martini, Alessandra C.;Rothermich, Winston Chang;Pascual, Jesse;Head, Elizabeth;Hume, David A.;Pridans, Clare;Davtyan, Hayk;Swarup, Vivek;Blurton-Jones, Mathew
小胶质细胞与阿尔茨海默病（AD）的发展和进展密切相关，但其对病理学和寿命的影响仍不清楚。在这里，我们利用CSF 1 R亚型小鼠产生的AD模型，遗传上缺乏小胶质细胞。由此产生的小胶质细胞缺陷小鼠表现出从实质淀粉样蛋白斑块到脑淀粉样蛋白血管病（CAA）的深刻转变，这伴随着许多转录变化、大大增加的脑钙化和钙化以及过早致死。值得注意的是，将野生型小胶质细胞单次注射到成年小鼠中可以重新填充小胶质细胞生态位并防止这些病理变化中的每一种。总之，这些结果表明小胶质细胞在减少CAA、血脑屏障功能障碍和脑钙化中的保护功能。为了进一步理解这些发现的临床意义，检查了人AD组织和iPSC-小胶质细胞，提供了小胶质细胞吞噬钙晶体的证据，并且该过程因AD风险基因TREM 2的丢失而受损。Kiani Shabestari等人表明，阿尔茨海默病小鼠中小胶质细胞的遗传缺失导致从实质淀粉样蛋白斑块转变为脑淀粉样蛋白血管病、脑钙化和脑萎缩以及过早致死。成人小胶质细胞移植挽救了这些病理变化，表明小胶质细胞保护大脑免受有害的阿尔茨海默病共同病理。
Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2. Kiani Shabestari et al. show that genetic absence of microglia in Alzheimer’s disease mice causes a shift from parenchymal amyloid plaques to cerebral amyloid angiopathy, brain calcification and hemorrhages, and premature lethality. Adult microglial transplantation rescues these pathological changes, demonstrating that microglia protect the brain against detrimental Alzheimer’s disease co-pathologies.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
13.6
作者：
Da Mesquita S;Herz J;Wall M;Dykstra T;de Lima KA;Norris GT;Dabhi N;Kennedy T;Baker W;Kipnis J
通讯作者：
Kipnis J
DOI：
10.1111/j.1749-6632.2002.tb04801.x
发表时间：
2002-01-01
期刊：
ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY
影响因子：
--
作者：
Buckwalter, M;Pepper, JP;Wyss-Coray, T
通讯作者：
Wyss-Coray, T
影响因子：
4.4
作者：
Grabert, Kathleen;Sehgal, Anuj;Hume, David A.
通讯作者：
Hume, David A.
影响因子：
4.2
作者：
D'Andrea, MR;Cole, GM;Ard, MD
通讯作者：
Ard, MD