Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

Objective: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the epsilon 4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-beta deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. Methods: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. Results: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by similar to 50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. Interpretation: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021

Automated summary

Therapeutic reduction of ApoE4 levels through ASO treatment showed significant protective effects on tau pathology, neurodegeneration, neuroinflammation, and synaptic density, indicating a potential therapeutic approach for APOE4 carriers with tauopathy, including Alzheimer's disease.