Neuronal APOE4 removal strongly protects against Tau-mediated gliosis, neurodegeneration, and myelin deficits

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the exact roles of neuronal APOE4 in AD pathogenesis are still unclear. Here we report a rigorous characterization of neuronal APOE4 effects on prominent AD-related pathologies by selectively removing APOE4 from neurons in an APOE4-expressing tauopathy mouse model. We found that the removal of neuronal APOE4 led to a drastic reduction in Tau pathology accumulation and spread, gliosis, neurodegeneration, neurodysfunction, and myelin deficits in this tauopathy mouse model. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes, and microglia that were enriched in APOE4-expressing tauopathy mice and whose accumulation correlated to the severity of Tau pathology, neurodegeneration, and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can effectively combat APOE4-driven effects in AD and other tauopathies. Single-nucleus RNA sequencing on isolated hippocampi from 10-month-old PS19-fE4 mice with or without Syn1-Cre and PS19-fE3 mice.