UCSF

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Within the central nervous system (CNS), APOE is produced by a variety of cell types under different conditions. It has become evident that the APOE4 produced in different CNS cells plays differential roles in AD pathogenesis. In particular, studies have shown that APOE4 produced by neurons plays a central role in promoting the development of major AD pathologies such as tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability, and myelin deficits, highlighting its ability to influence other CNS cells and its role as an upstream factor either directly or indirectly affecting numerous downstream AD-related cell types, genes, and pathways. Here we demonstrate that targeted reduction of a neuron-specific splicing variant of APOE mRNA (APOE-I3) using antisense oligonucleotides (ASOs) effectively reduces APOE expression in neurons in vitro and in vivo. Treating PS19 tauopathy mice expressing APOE4 with this APOE-I3-ASO rescues neurodegeneration and alters tau-mediated gliosis patterns. Single-nucleus RNA sequencing demonstrated that APOE-I3-ASO treatment promotes healthy neuronal clusters and diminishes disease associated neuronal and glial clusters. These findings suggest that preferential knockdown of neuronal APOE4 with ASO protects against key hallmarks of AD pathology, and elucidates a potential therapeutic approach for APOE4-driven AD.