Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model
| العنوان: | Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model |
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| المؤلفون: | Gaston Habets, Parmveer Singh, Gideon Bollag, Brian L. West, Lindsay A. Hohsfield, Andrey Rymar, Prabha N. Ibrahim, Stephanie Broome, Joshua D. Crapser, Garson Tsang, Elizabeth E. Spangenberg, Marika Nespi, Elizabeth A. Burton, Paul Severson, Jason Walters, Kim N. Green, Chao Zhang, Jack Lin, Jiazhong Zhang, Wayne Spevak, Ying Zhang, Nicole Y. Phan |
| المصدر: | Nature communications, vol 10, iss 1 Nature Communications, Vol 10, Iss 1, Pp 1-21 (2019) Nature Communications |
| بيانات النشر: | eScholarship, University of California, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Aging, General Physics and Astronomy, Hippocampus, Plaque, Amyloid, 02 engineering and technology, Neurodegenerative, Alzheimer's Disease, Transgenic, Pathogenesis, Mice, Gene expression, Receptors, 2.1 Biological and endogenous factors, Organic Chemicals, Aetiology, lcsh:Science, Receptor, Plaque, Regulation of gene expression, Multidisciplinary, Behavior, Animal, Microglia, Brain, Alzheimer's disease, 021001 nanoscience & nanotechnology, Cell biology, medicine.anatomical_structure, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Neurological, Cerebral amyloid angiopathy, 0210 nano-technology, Amyloid, Science, Transgene, Mice, Transgenic, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Alzheimer Disease, Memory, medicine, Genetics, Acquired Cognitive Impairment, Animals, Humans, Behavior, Animal, Neurosciences, Granulocyte-Macrophage Colony-Stimulating Factor, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), General Chemistry, medicine.disease, Brain Disorders, Disease Models, Animal, 030104 developmental biology, nervous system, Gene Expression Regulation, Disease Models, lcsh:Q, Dementia, Transcriptome |
| الوصف: | Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis. Genetics implicate microglia in Alzheimer’s disease pathogenesis, but their roles remain unclear. Here, the authors find that microglial depletion in a mouse model of Alzheimer’s disease impairs plaque formation and that Aβ-induced changes in neuronal gene expression are microglia-mediated. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed40cee7378de96501838a791a1537ee https://escholarship.org/uc/item/6062s7cq |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ed40cee7378de96501838a791a1537ee |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |