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

Abstract

OBJECTIVE:

Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β 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 ~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;89:952-966.

• Authors: Alexandra Litvinchuk, Tien-Phat V Huynh, Yang Shi, Rosemary J Jackson, Mary B Finn, Melissa Manis, Caroline M Francis, Ainsley C Tran, Patrick M Sullivan, Jason D Ulrich, Bradley T Hyman, Tracy Cole, David M Holtzman
• Journal: Annals of neurology (Ann Neurol) Vol. 89 Issue 5 Pg. 952-966 (05 2021) ISSN: 1531-8249 [Electronic] United States
• PMID: 33550655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Neurological Association.

Chemical References

• Apolipoprotein E4
• Mapt protein, mouse
• Neurofilament Proteins
• Oligonucleotides, Antisense
• tau Proteins
• Cholesterol

Topics

• Animals
• Apolipoprotein E4 (antagonists & inhibitors, blood, genetics)
• Cholesterol (metabolism)
• Dentate Gyrus (pathology)
• Encephalitis (prevention & control)
• Gene Knock-In Techniques
• Injections, Intraventricular
• Mice
• Mice, Inbred C57BL
• Neurodegenerative Diseases (drug therapy, etiology)
• Neurofilament Proteins (metabolism)
• Oligonucleotides, Antisense (administration & dosage, therapeutic use)
• Synapses (drug effects, pathology)
• Tauopathies (complications, drug therapy)
• tau Proteins (metabolism)