Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes

Won Suk Chung, Philip B. Verghese, Chandrani Chakraborty, Julia Joung, Bradley T. Hyman, Jason D. Ulrich, David M. Holtzman, Ben A. Barres

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

The strongest genetic risk factor influencing susceptibility to lateonset 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 C1qcoated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.

Original languageEnglish
Pages (from-to)10186-10191
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number36
DOIs
StatePublished - Sep 6 2016

Keywords

  • Apoe allele
  • Astrocytes|synapse elimination|phagocytosis |c1q

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