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

Abstract

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.

Authors:
 [1];  [2];  [1];  [1];  [2];  [2];  [2];  [2];  [2];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2] more »; ORCiD logo [2];  [1] « less
  1. Univ. of California, Irvine, CA (United States)
  2. Plexxikon Inc, Berkeley, CA, (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1624183
Grant/Contract Number:  
AC02-05CH11231; R01NS083801; R01AG056768; P50AG016573; AARF-16–442762; F31AG059367; T32AG00096
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics

Citation Formats

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., and Green, Kim N.. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. United States: N. p., 2019. Web. https://doi.org/10.1038/s41467-019-11674-z.
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.. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. United States. https://doi.org/10.1038/s41467-019-11674-z
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., and Green, Kim N.. Wed . "Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model". United States. https://doi.org/10.1038/s41467-019-11674-z. https://www.osti.gov/servlets/purl/1624183.
@article{osti_1624183,
title = {Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model},
author = {Spangenberg, Elizabeth and Severson, Paul L. and Hohsfield, Lindsay A. and Crapser, Joshua and Zhang, Jiazhong and Burton, Elizabeth A. and Zhang, Ying and Spevak, Wayne and Lin, Jack and Phan, Nicole Y. and Habets, Gaston and Rymar, Andrey and Tsang, Garson and Walters, Jason and Nespi, Marika and Singh, Parmveer and Broome, Stephanie and Ibrahim, Prabha and Zhang, Chao and Bollag, Gideon and West, Brian L. and Green, Kim N.},
abstractNote = {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.},
doi = {10.1038/s41467-019-11674-z},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {8}
}

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Figures / Tables:

Fig. 1 Fig. 1: Plaque-distal microglia contain aggregated Aβ. a–e 15-month-old 3xTg-AD mice were stained for dense core deposits with Thio-S (in green), and immunolabeled for microglia (IBA1 in red) and macrophage lysosomes (CD68 in blue; a, c, and e) with zoomed image (b) of Thio-S+ material within microglia and within lysosomes,more » separately. Scale bars= 20 μm for a, e 5 μm for b, 10 μm for c. d, f Three-dimensional reconstruction of microglia (IBA1 in red), the microglial lysosome (CD68 in purple), and fibrillar Aβ (Thio-S in green), demonstrating the localization of Aβ to the microglial lysosome in non-plaque associated microglia. Scale bars= 7 μm. gj 5xFAD animals stained for dense-core deposits (Thio-S in green) and immunolabeled for microglia (IBA1 in red; g and i), with zoomed images (h, j) demonstrating Thio-S+ aggregates in microglial cell bodies in 4- and 7-month-old 5xFAD mice. Scale bars= 40 μm for g, i 10 μm for h, j« less

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