Apolipoprotein E4 Exacerbates Aβ Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4

APOE4 amplifies Aβ oligomer–induced synaptotoxicity in primary neuronal cultures by lowering SOCE and STIM1, with downstream Gpx4 autophagic degradation linked to ROS buildup and mitochondrial cristae disruption.

• Why it matters: Synaptic loss in Alzheimer’s disease is strongly associated with soluble Aβ oligomers, but how APOE4 worsens synaptic failure—particularly through calcium signaling and autophagy—remains unclear.
• What they did: Primary neurons were co-treated with Aβ oligomers and APOE4 versus APOE3 or APOE2, then assessed synapse density, dendritic arbor complexity, SOCE amplitudes, STIM1/STIM2, and p62-dependent autophagic pathways; STIM1 overexpression and Gpx4-related readouts were used to test rescue and mechanism.
• The result: Aβ oligomers plus APOE4 reduced synapse density, dendritic complexity, SOCE amplitudes, and STIM1 protein via p62-selective autophagic degradation, which initiated Bcl2-linked Gpx4 autophagic degradation, increasing reactive oxygen species and disrupting mitochondrial cristae morphology.

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