Abstract
Neuroscience. 2026 Sep 18:S0306-4522(26)00635-4. doi: 10.1016/j.neuroscience.2026.09.026. Online ahead of print.
ABSTRACT
APOE gene variants encoding the apolipoprotein E (ApoE) protein are strong genetic modifiers of risk of Alzheimer's disease (AD) with the APOE ε4 allele (APOE4) associated with substantially increased disease risk, APOE ε2 allele (APOE2) associated with decreased risk and APOE ε3 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. Human APOE expressing mouse 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.
PMID:42759807 | DOI:10.1016/j.neuroscience.2026.09.026