C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease

被引：6

作者：

Gomez-Arboledas, Angela ^{[1
]}

Fonseca, Maria I. ^{[1
]}

Kramar, Eniko ^{[2
]}

Chu, Shu-Hui ^{[1
]}

Schartz, Nicole D. ^{[1
]}

Selvan, Purnika ^{[1
]}

Wood, Marcelo A. ^{[2
]}

Tenner, Andrea J. ^{[1
,2
,3
]}

机构：

[1] Univ Calif Irvine, Dept Mol Biol & Biochem, 3205 McGaugh Hall, Irvine, CA 92697 USA

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

[3] Univ Calif Irvine, Sch Med, Dept Pathol & Lab Med, Irvine, CA 92697 USA

来源：

ALZHEIMERS & DEMENTIA | 2024年 / 20卷 / 03期

关键词：

Alzheimer's disease; C1q; C5aR1; LTP; microglia; synaptic pruning; ALZHEIMERS-DISEASE; COMPLEMENT ACTIVATION; MOUSE MODELS; MURINE MODELS; C1Q; EXPRESSION; MICROGLIA; RECEPTOR; ELIMINATION; AMYLOIDOSIS;

D O I：

10.1002/alz.13682

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

INTRODUCTION: Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODS: A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTS: Genetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). DISCUSSION: Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.

引用

页码：2173 / 2190

页数：18

共 71 条

[51] Schizophrenia risk from complex variation of complement component 4 [J].

Sekar, Aswin ;

Bialas, Allison R. ;

de Rivera, Heather ;

Davis, Avery ;

Hammond, Timothy R. ;

Kamitaki, Nolan ;

Tooley, Katherine ;

Presumey, Jessy ;

Baum, Matthew ;

Van Doren, Vanessa ;

Genovese, Giulio ;

Rose, Samuel A. ;

Handsaker, Robert E. ;

Daly, Mark J. ;

Carroll, Michael C. ;

Stevens, Beth ;

McCarroll, Steven A. .

NATURE, 2016, 530 (7589) :177-+

[52] Alzheimer's disease is a synaptic failure [J].

Selkoe, DJ .

SCIENCE, 2002, 298 (5594) :789-791

[53] Complement activation by neurofibrillary tangles in Alzheimer's disease [J].

Shen, Y ;

Lue, LF ;

Yang, LB ;

Roher, A ;

Kuo, YM ;

Strohmeyer, R ;

Goux, WJ ;

Lee, V ;

Johnson, GVW ;

Webster, SD ;

Cooper, NR ;

Bradt, B ;

Rogers, J .

NEUROSCIENCE LETTERS, 2001, 305 (03) :165-168

[54] Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice [J].

Shi, Qiaoqiao ;

Chowdhury, Saba ;

Ma, Rong ;

Le, Kevin X. ;

Hong, Soyon ;

Caldarone, Barbara J. ;

Stevens, Beth ;

Lemere, Cynthia A. .

SCIENCE TRANSLATIONAL MEDICINE, 2017, 9 (392)

[55]

Sokolova Dimitra, 2021, Fac Rev, V10, P19, DOI 10.12703/r/10-19

[56] A Dramatic Increase of C1q Protein in the CNS during Normal Aging [J].

Stephan, Alexander H. ;

Madison, Daniel V. ;

Mateos, Jose Maria ;

Fraser, Deborah A. ;

Lovelett, Emilie A. ;

Coutellier, Laurence ;

Kim, Leo ;

Tsai, Hui-Hsin ;

Huang, Eric J. ;

Rowitch, David H. ;

Berns, Dominic S. ;

Tenner, Andrea J. ;

Shamloo, Mehrdad ;

Barres, Ben A. .

JOURNAL OF NEUROSCIENCE, 2013, 33 (33) :13460-13474

[57] The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease [J].

Stephan, Alexander H. ;

Barres, Ben A. ;

Stevens, Beth .

ANNUAL REVIEW OF NEUROSCIENCE, VOL 35, 2012, 35 :369-389

[58] The classical complement cascade mediates CNS synapse elimination [J].

Stevens, Beth ;

Allen, Nicola J. ;

Vazquez, Luis E. ;

Howell, Gareth R. ;

Christopherson, Karen S. ;

Nouri, Navid ;

Micheva, Kristina D. ;

Mehalow, Adrienne K. ;

Huberman, Andrew D. ;

Stafford, Benjamin ;

Sher, Alexander ;

Litke, Alan M. ;

Lambris, John D. ;

Smith, Stephen J. ;

John, Simon W. M. ;

Barres, Ben A. .

CELL, 2007, 131 (06) :1164-1178

[59] A synthetic synaptic organizer protein restores glutamatergic neuronal circuits [J].

Suzuki, Kunimichi ;

Elegheert, Jonathan ;

Song, Inseon ;

Sasakura, Hiroyuki ;

Senkov, Oleg ;

Matsuda, Keiko ;

Kakegawa, Wataru ;

Clayton, Amber J. ;

Chang, Veronica T. ;

Ferrer-Ferrer, Maura ;

Miura, Eriko ;

Kaushik, Rahul ;

Ikeno, Masashi ;

Morioka, Yuki ;

Takeuchi, Yuka ;

Shimada, Tatsuya ;

Otsuka, Shintaro ;

Stoyanov, Stoyan ;

Watanabe, Masahiko ;

Takeuchi, Kosei ;

Dityatev, Alexander ;

Aricescu, A. Radu ;

Yuzaki, Michisuke .

SCIENCE, 2020, 369 (6507) :1074-+

[60]

Veerhuis R, 1996, ACTA NEUROPATHOL, V91, P53

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