Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia

被引：202

作者：

Wang, Chao ^{[1
]}

Xiong, Monica ^{[1
]}

Gratuze, Maud ^{[1
]}

Bao, Xin ^{[1
]}

Shi, Yang ^{[1
]}

Andhey, Prabhakar Sairam ^{[2
]}

Manis, Melissa ^{[1
]}

Schroeder, Caitlin ^{[3
]}

Yin, Zhuoran ^{[3
]}

Madore, Charlotte ^{[3
]}

Butovsky, Oleg ^{[3
,4
]}

Artyomov, Maxim ^{[2
]}

Ulrich, Jason D. ^{[1
]}

Holtzman, David M. ^{[1
]}

机构：

[1] Washington Univ, Hope Ctr Neurol Disorders, Res Ctr, Dept Neurol,Knight Alzheimer Dis, St Louis, MO 63110 USA

[2] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[4] Harvard Med Sch, Evergrande Ctr Immunol Dis, Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

NEURON | 2021年 / 109卷 / 10期

基金：

美国国家卫生研究院;

关键词：

APOLIPOPROTEIN-E; BINDING; METABOLISM; PATHOLOGY; DISEASE; ABCA1; AD;

D O I：

10.1016/j.neuron.2021.03.024

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3(flox/flox) or Tau/Aldh1l1-CreERT2/apoE4(flox/flox) mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.

引用

页码：1657 / +

页数：25

共 72 条

[1] Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo [J].

Apicco, Daniel J. ;

Ash, Peter E. A. ;

Maziuk, Brandon ;

LeBlang, Chelsey ;

Medalla, Maria ;

Al Abdullatif, Ali ;

Ferragud, Antonio ;

Botelho, Emily ;

Ballance, Heather I. ;

Dhawan, Uma ;

Boudeau, Samantha ;

Cruz, Anna Lourdes ;

Kashy, Daniel ;

Wong, Aria ;

Goldberg, Lisa R. ;

Yazdani, Neema ;

Zhang, Cheng ;

Ung, Choong Y. ;

Tripodis, Yorghos ;

Kanaan, Nicholas M. ;

Ikezu, Tsuneya ;

Cottone, Pietro ;

Leszyk, John ;

Li, Hu ;

Luebke, Jennifer ;

Bryant, Camron D. ;

Wolozin, Benjamin .

NATURE NEUROSCIENCE, 2018, 21 (01) :72-+

[2]

Arendt T, 1997, J NEUROSCI, V17, P516

[3] Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) [J].

Atagi, Yuka ;

Liu, Chia-Chen ;

Painter, Meghan M. ;

Chen, Xiao-Fen ;

Verbeeck, Christophe ;

Zheng, Honghua ;

Li, Xia ;

Rademakers, Rosa ;

Kang, Silvia S. ;

Xu, Huaxi ;

Younkin, Steven ;

Das, Pritam ;

Fryer, John D. ;

Bu, Guojun .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (43) :26043-26050

[4] U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease [J].

Bai, Bing ;

Hales, Chadwick M. ;

Chen, Ping-Chung ;

Gozal, Yair ;

Dammer, Eric B. ;

Fritz, Jason J. ;

Wang, Xusheng ;

Xia, Qiangwei ;

Duong, Duc M. ;

Street, Craig ;

Cantero, Gloria ;

Cheng, Dongmei ;

Jones, Drew R. ;

Wu, Zhiping ;

Li, Yuxin ;

Diner, Ian ;

Heilman, Craig J. ;

Rees, Howard D. ;

Wu, Hao ;

Lin, Li ;

Szulwach, Keith E. ;

Gearing, Marla ;

Mufson, Elliott J. ;

Bennett, David A. ;

Montine, Thomas J. ;

Seyfried, Nicholas T. ;

Wingo, Thomas S. ;

Sun, Yi E. ;

Jin, Peng ;

Hanfelt, John ;

Willcock, Donna M. ;

Levey, Allan ;

Lah, James J. ;

Peng, Junmin .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (41) :16562-16567

[5] Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease [J].

Bejanin, Alexandre ;

Schonhaut, Daniel R. ;

La Joie, Renaud ;

Kramer, Joel H. ;

Baker, Suzanne L. ;

Sosa, Natasha ;

Ayakta, Nagehan ;

Cantwell, Averill ;

Janabi, Mustafa ;

Lauriola, Mariella ;

O'Neil, James P. ;

Gorno-Tempini, Maria L. ;

Miller, Zachary A. ;

Rosen, Howard J. ;

Miller, Bruce L. ;

Jagust, William J. ;

Rabinovici, Gil D. .

BRAIN, 2017, 140 :3286-3300

[6] Apolipoprotein E controls cerebrovascular integrity via cyclophilin A [J].

Bell, Robert D. ;

Winkler, Ethan A. ;

Singh, Itender ;

Sagare, Abhay P. ;

Deane, Rashid ;

Wu, Zhenhua ;

Holtzman, David M. ;

Betsholtz, Christer ;

Armulik, Annika ;

Sallstrom, Jan ;

Berk, Bradford C. ;

Zlokovic, Berislav V. .

NATURE, 2012, 485 (7399) :512-516

[7] Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice [J].

Brecht, WJ ;

Harris, FM ;

Chang, SJ ;

Tesseur, I ;

Yu, GQ ;

Xu, Q ;

Fish, JD ;

Wyss-Coray, T ;

Buttini, M ;

Mucke, L ;

Mahley, RW ;

Huang, YD .

JOURNAL OF NEUROSCIENCE, 2004, 24 (10) :2527-2534

[8] Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline [J].

Bussian, Tyler J. ;

Aziz, Asef ;

Meyer, Charlton F. ;

Swenson, Barbara L. ;

van Deursen, Jan M. ;

Baker, Darren J. .

NATURE, 2018, 562 (7728) :578-+

[9] Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].

Butler, Andrew ;

Hoffman, Paul ;

Smibert, Peter ;

Papalexi, Efthymia ;

Satija, Rahul .

NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+

[10] Targeting miR-155 Restores Abnormal Microglia and Attenuates Disease in SOD1 Mice [J].

Butovsky, Oleg ;

Jedrychowski, Mark P. ;

Cialic, Ron ;

Krasemann, Susanne ;

Murugaiyan, Gopal ;

Fanek, Zain ;

Greco, David J. ;

Wu, Pauline M. ;

Doykan, Camille E. ;

Kiner, Olga ;

Lawson, Robert J. ;

Frosch, Matthew P. ;

Pochet, Nathalie ;

El Fatimy, Rachid ;

Krichevsky, Anna M. ;

Gygi, Steven P. ;

Lassmann, Hans ;

Berry, James ;

Cudkowicz, Merit E. ;

Weiner, Howard L. .

ANNALS OF NEUROLOGY, 2015, 77 (01) :75-99

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