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

被引：578

作者：

Spangenberg, Elizabeth ^{[1
]}

Severson, Paul L. ^{[2
]}

Hohsfield, Lindsay A. ^{[1
]}

Crapser, Joshua ^{[1
]}

Zhang, Jiazhong ^{[2
]}

Burton, Elizabeth A. ^{[2
]}

Zhang, Ying ^{[2
]}

Spevak, Wayne ^{[2
]}

Line, Jack ^{[2
]}

Phan, Nicole Y. ^{[1
]}

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
]}

West, Brian L. ^{[2
]}

Green, Kim N. ^{[1
]}

机构：

[1] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

[2] Plexxikon Inc, Berkeley, CA 94710 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

AMYLOID-BETA-PROTEIN; A-BETA; TRANSGENIC MICE; MYELOID CELLS; NEURONAL LOSS; PREVENTS; BRAIN; TREM2; ONSET; ACCUMULATION;

D O I：

10.1038/s41467-019-11674-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 brainpenetrant 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, Ap 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 plaqueforming 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.

引用

页数：21

共 70 条

[1] Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease [J].

Andrew, Robert J. ;

Fernandez, Celia G. ;

Stanley, Molly ;

Jiang, Hong ;

Phuong Nguyen ;

Rice, Richard C. ;

Buggia-Prevot, Virginie ;

De Rossi, Pierre ;

Vetrivel, Kulandaivelu S. ;

Lamb, Raza ;

Argemi, Arnau ;

Allaert, Emilie S. ;

Rathbun, Elle M. ;

Krause, Sofia V. ;

Wagner, Steven L. ;

Parent, Angele T. ;

Holtzman, David M. ;

Thinakaran, Gopal .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (45) :E9665-E9674

[2]

[Anonymous], EMBO J

[3]

[Anonymous], 2017, R LANG ENV STAT COMP

[4]

[Anonymous], BR J PHARM

[5]

[Anonymous], GLIA

[6]

[Anonymous], NAT NEUROSCI

[7]

[Anonymous], CELL

[8] Microglia Contributes to Plaque Growth by Cell Death Due to Uptake of Amyloid β in the Brain of Alzheimer's Disease Mouse Model [J].

Baik, Sung Hoon ;

Kang, Seokjo ;

Son, Sung Min ;

Mook-Jung, Inhee .

GLIA, 2016, 64 (12) :2274-2290

[9] Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease [J].

Bateman, Randall J. ;

Aisen, Paul S. ;

De Strooper, Bart ;

Fox, Nick C. ;

Lemere, Cynthia A. ;

Ringman, John M. ;

Salloway, Stephen ;

Sperling, Reisa A. ;

Windisch, Manfred ;

Xiong, Chengjie .

ALZHEIMERS RESEARCH & THERAPY, 2011, 3 (01)

[10] Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System [J].

Bruttger, Julia ;

Karram, Khalad ;

Woertge, Simone ;

Regen, Tommy ;

Marini, Federico ;

Hoppmann, Nicola ;

Klein, Matthias ;

Blank, Thomas ;

Yona, Simon ;

Wolf, Yochai ;

Mack, Matthias ;

Pinteaux, Emmanuel ;

Mueller, Werner ;

Zipp, Frauke ;

Binder, Harald ;

Bopp, Tobias ;

Prinz, Marco ;

Jung, Steffen ;

Waisman, Ari .

IMMUNITY, 2015, 43 (01) :92-106

← 1 2 3 4 5 6 7 →