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Proc. Natl. Acad. Sci. USA, Published online before print August 24, 2016, doi: 10.1073/pnas.1609896113
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Abstract
Won-Suk Chunga,1, Philip B. Vergheseb,2, Chandrani Chakrabortya, Julia Jounga,3, Bradley T. Hymanc,d, Jason D. Ulrichb, David M. Holtzmanb, and Ben A. Barresa,4
aDepartment of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305;
bDepartment of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110;
cMassachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, MA 02129;
dDepartment of Neurology, Massachusetts General Hospital, Boston, MA 02129
Abstract
The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.
Abstract
The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.
1To whom correspondence may be addressed at the present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea.
2Present address: C2N Diagnostics, Center for Emerging Technologies, 4041 Forest Park Avenue, Saint Louis, MO 63108.
3Present address: Broad Institute of MIT and Harvard, Cambridge, MA 02142; McGovern Institute for Brain Research, Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
4To whom correspondence may be addressed.
논문정보
- Research article
- 2016년 08월 (BRIC 등록일 2016-08-30)
- 국외 연구진
- 생명과학 > 신경생물학
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