Astrocytic Synapse Engulfment Is Differentially Controlled by APOE Genotype

APOE gene variants encoding the apolipoprotein E (ApoE) protein are strong genetic modifiers of risk of Alzheimers disease (AD) with the APOE {varepsilon}4 allele (APOE4) associated with substantially increased disease risk, APOE {varepsilon}2 allele (APOE2) associated with decreased risk and APOE {varepsilon}3 allele (APOE3) considered neutral. Recently the Christchurch variant of APOE3 (APOE3Ch) has been shown to protect people from familial AD. Despite this strong evidence for APOE mediating AD risk, the exact biological mechanisms through which APOE influences pathogenesis remain unknown. Our previous work implicates APOE in synapse degeneration in AD with exacerbated plaque-associated synapse loss, increased accumulation of amyloid beta in synapses, and increased ingestion of synapses by glia around plaques observed in APOE4 carriers. Here we used a cell culture system to test the hypothesis that APOE isoforms would differentially regulate phagocytosis of synapses isolated from human post-mortem AD brain tissue. Humanized APOE knock-in astrocyte cell lines exhibited isoform-dependent differences in phagocytic activity with APOE2 < APOE3 < APOE4 as would be expected if APOE genotype mediated risk at least in part through synapse phagocytosis. Interestingly, astrocytes with the protective APOE3Ch allele phagocytosed synapses similarly to APOE4 astrocytes indicating this variant does not likely protect from AD by reducing astrocyte phagocytosis of synapses. These findings indicate that APOE isoforms differentially regulate astrocytic engulfment of AD-associated synaptic material. These isoform-specific effects are not explained by differences in phosphatidylserine recognition, suggesting the involvement of additional mechanisms underlying ApoE-dependent modulation of astrocyte function. Significance StatementSekizar and colleagues tested whether APOE, the most important genetic risk factor for Alzheimers disease, could affect risk by influencing the ability of astrocytes to phagocytose synapses. Using astrocyte cell lines exposed to synapses isolated from Alzheimers disease brain tissue, they demonstrate that different APOE isoforms differentially modulate astrocyte-mediated synapse phagocytosis. These results will inform future work to develop therapies that aim to preserve synapses in Alzheimers disease.