Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

Spangenberg, Elizabeth; Severson, Paul L.; Hohsfield, Lindsay A.; Crapser, Joshua; Zhang, Jiazhong; Burton, Elizabeth A.; Zhang, Ying; Spevak, Wayne; Lin, Jack; Phan, Nicole Y.; Habets, Gaston; Rymar, Andrey; Tsang, Garson; Walters, Jason; Nespi, Marika; Singh, Parmveer; Broome, Stephanie; Ibrahim, Prabha; Zhang, Chao; Bollag, Gideon; West, Brian L.; Green, Kim N.

doi:10.1038/s41467-019-11674-z

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

Journal Article · Wed Aug 21 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-11674-z· OSTI ID:1624183

Spangenberg, Elizabeth ^[1]; Severson, Paul L. ^[2]; Hohsfield, Lindsay A. ^[3]; Crapser, Joshua ^[3]; Zhang, Jiazhong ^[2]; Burton, Elizabeth A. ^[2]; Zhang, Ying ^[2]; Spevak, Wayne ^[2]; Lin, Jack ^[2]; Phan, Nicole Y. ^[3]; Habets, Gaston ^[2]; Rymar, Andrey ^[2]; Tsang, Garson ^[2]; Walters, Jason ^[2]; Nespi, Marika ^[2]; Singh, Parmveer ^[2]; Broome, Stephanie ^[2]; Ibrahim, Prabha ^[2]; Zhang, Chao ^[2]; Bollag, Gideon ^[2] more »

Univ. of California, Irvine, CA (United States); DOE/OSTI
Plexxikon Inc, Berkeley, CA, (United States)
Univ. of California, Irvine, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624183

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Additional file 4 of Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia Benitez, Diana P.; Jiang, Shenyi; Wood, Jack figshare https://doi.org/10.6084/m9.figshare.14992876	image	January 2021
Additional file 5 of Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia Benitez, Diana P.; Jiang, Shenyi; Wood, Jack figshare https://doi.org/10.6084/m9.figshare.14992879	image	January 2021
Additional file 6 of Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia Benitez, Diana P.; Jiang, Shenyi; Wood, Jack figshare https://doi.org/10.6084/m9.figshare.14992882.v1	image	January 2021
Additional file 1 of Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease Shin, Hyo Jung; Kim, In Soo; Choi, Seung Gyu figshare https://doi.org/10.6084/m9.figshare.25424750.v1	image	January 2024
Additional file 1 of CSF1R antagonism results in increased supraspinal infiltration in EAE Wang, Marilyn; Caryotakis, Sofia E.; Smith, Glendalyn G. figshare https://doi.org/10.6084/m9.figshare.25658576.v1	image	January 2024
Microwave-assisted synthesis of 7-azaindoles via iron-catalyzed cyclization of an o -haloaromatic amine with terminal alkynes Le, Yi; Yang, Zhisong; Chen, Yumei RSC Advances, Vol. 9, Issue 68 https://doi.org/10.1039/c9ra08742g	journal	January 2019
Death by microglia Kemal, Shahrnaz; Vassar, Robert Journal of Experimental Medicine, Vol. 216, Issue 11 https://doi.org/10.1084/jem.20191536	journal	October 2019
Mitigation of helium irradiation-induced brain injury by microglia depletion Allen, Barrett D.; Syage, Amber R.; Maroso, Mattia Journal of Neuroinflammation, Vol. 17, Issue 1 https://doi.org/10.1186/s12974-020-01790-9	journal	May 2020
Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE Hu, Xiao; Li, Shirong; Doycheva, Desislava Met Journal of Neuroinflammation, Vol. 17, Issue 1 https://doi.org/10.1186/s12974-020-01862-w	journal	June 2020
Flow-cytometric microglial sorting coupled with quantitative proteomics identifies moesin as a highly-abundant microglial protein with relevance to Alzheimer’s disease Rayaprolu, Sruti; Gao, Tianwen; Xiao, Hailian Molecular Neurodegeneration, Vol. 15, Issue 1 https://doi.org/10.1186/s13024-020-00377-5	journal	May 2020
Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice Eede, Pascale; Obst, Juliane; Benke, Eileen EMBO reports, Vol. 21, Issue 3 https://doi.org/10.15252/embr.201948530	journal	January 2020

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Additional file 1 of Microglia as target for anti-inflammatory approaches to prevent secondary brain injury after subarachnoid hemorrhage (SAH) Heinz, Rebecca; Brandenburg, Susan; Nieminen-Kelhä, Melina https://doi.org/10.6084/m9.figshare.13669573 The current record is supplemented by this text	text	January 2021
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