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Articles, Development/Plasticity/Repair

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Alexander H. Stephan, Daniel V. Madison, José María Mateos, Deborah A. Fraser, Emilie A. Lovelett, Laurence Coutellier, Leo Kim, Hui-Hsin Tsai, Eric J. Huang, David H. Rowitch, Dominic S. Berns, Andrea J. Tenner, Mehrdad Shamloo and Ben A. Barres
Journal of Neuroscience 14 August 2013, 33 (33) 13460-13474; DOI: https://doi.org/10.1523/JNEUROSCI.1333-13.2013
Alexander H. Stephan
1Stanford University School of Medicine, Departments of Neurobiology and
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Daniel V. Madison
2Molecular and Cellular Physiology, Stanford, California 94305-5345,
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José María Mateos
3Center for Microscopy and Image Analysis, University of Zurich, 8057 Zurich, Switzerland,
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Deborah A. Fraser
4Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California 92697-3900,
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Emilie A. Lovelett
1Stanford University School of Medicine, Departments of Neurobiology and
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Laurence Coutellier
5Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California 94305-5345,
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Leo Kim
5Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California 94305-5345,
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Hui-Hsin Tsai
6Howard Hughes Medical Institute,
7Department of Pediatrics,
8Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and
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Eric J. Huang
9Department of Pathology, University of California San Francisco, San Francisco, California 94143-0734
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David H. Rowitch
6Howard Hughes Medical Institute,
7Department of Pediatrics,
8Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and
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Dominic S. Berns
1Stanford University School of Medicine, Departments of Neurobiology and
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Andrea J. Tenner
4Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California 92697-3900,
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Mehrdad Shamloo
5Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California 94305-5345,
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Ben A. Barres
1Stanford University School of Medicine, Departments of Neurobiology and
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Abstract

The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.

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The Journal of Neuroscience: 33 (33)
Journal of Neuroscience
Vol. 33, Issue 33
14 Aug 2013
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A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Alexander H. Stephan, Daniel V. Madison, José María Mateos, Deborah A. Fraser, Emilie A. Lovelett, Laurence Coutellier, Leo Kim, Hui-Hsin Tsai, Eric J. Huang, David H. Rowitch, Dominic S. Berns, Andrea J. Tenner, Mehrdad Shamloo, Ben A. Barres
Journal of Neuroscience 14 August 2013, 33 (33) 13460-13474; DOI: 10.1523/JNEUROSCI.1333-13.2013

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A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Alexander H. Stephan, Daniel V. Madison, José María Mateos, Deborah A. Fraser, Emilie A. Lovelett, Laurence Coutellier, Leo Kim, Hui-Hsin Tsai, Eric J. Huang, David H. Rowitch, Dominic S. Berns, Andrea J. Tenner, Mehrdad Shamloo, Ben A. Barres
Journal of Neuroscience 14 August 2013, 33 (33) 13460-13474; DOI: 10.1523/JNEUROSCI.1333-13.2013
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