Neuronal APOE4 reduction with an APOE-I3-targeting ASO protects against neurodegeneration and neuroinflammation in an Alzheimer's disease mouse model

Yip, O.; Yao, L.; Blumenfeld, J.; Kim, M. J.; Shostak, D.; Platow, Z.; Suan, K.; Li, Y.; Ellis, C.; An, A.; Hao, Y.; Xu, Q.; De Leon, S.; Nguyen, J.; Huang, Y.

doi:10.64898/2025.12.10.693468

bioRxiv · 10.64898/2025.12.10.693468

Neuronal APOE4 reduction with an APOE-I3-targeting ASO protects against neurodegeneration and neuroinflammation in an Alzheimer's disease mouse model

Yip, O.·Yao, L.·Blumenfeld, J.·Kim, M. J.·Shostak, D.·Platow, Z.·Suan, K.·Li, Y.·Ellis, C.·An, A.·Hao, Y.·Xu, Q.·De Leon, S.·Nguyen, J.·Huang, Y.

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Abstract

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease (AD). Within the central nervous system (CNS), APOE is produced by a variety of cell types, with differential roles in AD pathogenesis. Studies have shown that APOE4 produced by neurons plays a central role in promoting the development of major AD pathologies, including p-tau accumulation, neuroinflammation, and neurodegeneration, highlighting its role as an upstream initiating factor that affects other cell types and downstream AD-related pathologies. Here, we demonstrate that antisense oligonucleotides (ASOs) targeting APOE-I3, a neuron-specific splicing variant of APOE mRNA, effectively reduce APOE expression in neurons in vitro and in vivo. Treating PS19 tauopathy mice expressing APOE4 with this APOE-I3-targeting ASO reduces neuronal APOE4, rescues neurodegeneration, and diminishes neuroinflammation. Strikingly, the extent of neuronal APOE4 reduction predicts the efficacy of rescuing neurodegeneration. Single nucleus RNA-sequencing demonstrated that APOE-I3-targeting ASO treatment decreases disease associated neuronal and glial subtypes and increases a disease-protective microglial subtype. These findings suggest that preferential knockdown of neuronal APOE4 with an APOE-I3-targeting ASO protects against key hallmarks of AD pathology, elucidating a potential therapeutic approach for treating APOE4-driven AD.

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Yip, O., Yao, L., Blumenfeld, J., Kim, M. J., Shostak, D., Platow, Z., Suan, K., Li, Y., Ellis, C., An, A., Hao, Y., Xu, Q., De Leon, S., Nguyen, J., Huang, Y.. 2025-12-13. Neuronal APOE4 reduction with an APOE-I3-targeting ASO protects against neurodegeneration and neuroinflammation in an Alzheimer's disease mouse model. https://doi.org/10.64898/2025.12.10.693468

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