title: Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes.
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.
authors: Department of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305; wonsuk.chung@kaist.ac.kr.
authors: Won-Suk
authors: 0000-0003-1060-9007
authors: WS
authors: Chung
authors: Department 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;
authors: Philip B
authors: PB
authors: Verghese
authors: Department of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305;
authors: Chandrani
authors: C
authors: Chakraborty
authors: Department of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305;
authors: Julia
authors: J
authors: Joung
authors: Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Neurology, Massachusetts General Hospital, Boston, MA 02129.
authors: Bradley T
authors: BT
authors: Hyman
authors: Department 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;
authors: Jason D
authors: JD
authors: Ulrich
authors: Department 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;
authors: David M
authors: DM
authors: Holtzman
authors: Department of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305; barres@stanford.edu.
authors: Ben A
authors: BA
authors: Barres
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics* / Q000276:immunology; D053318:Apolipoprotein E3 / Q000235:genetics / Q000276:immunology; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000276:immunology; D001253:Astrocytes / Q000276:immunology* / Q000648:ultrastructure; D015922:Complement C1q / Q000235:genetics; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006624:Hippocampus / Q000276:immunology / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D010587:Phagocytosis; D013569:Synapses / Q000276:immunology / Q000648:ultrastructure
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D015922:Complement C1q
keywords: APOE allele; C1q; astrocytes; phagocytosis; synapse elimination