Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model
Open accessAbstract
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
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ApoE reduction at about 50% by apoE ASO treatment or LDLR overexpression is sufficient to alleviate the pathological changes in AD mouse models.
“apoE reduction at about 50% by apoE ASO treatment or LDLR overexpression is sufficient to alleviate the pathological changes in AD mouse models”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Litvinchuk et al 2021
The Results report that ASO treatment reduced ApoE4 by about 50–60% in P301S/ApoE4 tauopathy mice, and the Discussion reports reduced tau pathology and neurodegeneration. The paper does not report LDLR overexpression as a treatment, and its demonstrated benefit is specific to this tauopathy model rather than AD mouse models generally. Page numbers are not supplied in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAntisense oligonucleotides against APOE4 have been effective in mouse models of both Aβ plaque deposition and tauopathy, although the timing of administration seems to be crucial for success.
“Another mechanism of decreasing APOE4 expression is using antisense oligonucleotides against APOE4 (Fig. 3d). This method has been effective in mouse models of both Aβ plaque deposition and tauopathy, although the timing of administration seems to be crucial for success124,206.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [206]
Reduction of apoE4 protein levels by ~50% in the P301S/ApoE4 mouse model resulted in significant protection against tau pathology and associated neurodegeneration as well as inhibition of neuroinflammation.
“reduction of apoE4 protein levels by ~50% in the P301S/ApoE4 mouse model resulted in significant protection against tau pathology and associated neurodegeneration as well as inhibition of neuroinflammation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Litvinchuk et al 2021
Administration of ApoE-targeted ASO in an ApoE4-expressing mouse model of tauopathy protected against tau-associated neurodegeneration and other neuropathological features, namely synaptic disruption and neuroinflammation.
“The administration of ApoE-targeted ASO in an ApoE4-expressing mouse model of tauopathy, which is defined by the tau pathology common to AD, was also demonstrated to protect against tau-associated neurodegeneration and other neuropathological features of this disease, namely synaptic disruption and neuroinflammation [83].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [83]
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- Authors
- Litvinchuk, A., Huynh, T. V., Shi, Y., Jackson, R. J., Finn, M. B., Manis, M., Francis, C. M., Tran, A. C., Sullivan, P. M., Ulrich, J. D., Hyman, B. T., Cole, T., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Harvard University (US)
- Veterans Health Administration (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2021-02-24
- Volume
- 89
- Issue
- 5
- Pages
- 952-966
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC8260038
- OpenAlex
- W3127668400
- Cited by
- 91
- References
- 63
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 20 · 2023: 9 · 2022: 17 · 2021: 6
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- JPB Foundation
- National Institutes of Health (AG047644, NS090932)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, antisense oligonucleotides, tauopathy, tau pathology, neurodegeneration, neuroinflammation, synaptic density, neurofilament light chain, Alzheimer's disease, APOE ε4 carriers, gene silencing therapy
- MeSH terms
- Animals, Cholesterol, Encephalitis, Injections, Intraventricular, Mice, Inbred C57BL, Synapses, Oligonucleotides, Antisense, tau Proteins, Neurofilament Proteins, Dentate Gyrus, Neurodegenerative Diseases, Tauopathies, Mice, Apolipoprotein E4, Gene Knock-In Techniques
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