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dc.contributor.authorFerguson, Chantal M.
dc.contributor.authorHildebrand, Samuel
dc.contributor.authorGodinho, Bruno M D C
dc.contributor.authorBuchwald, Julianna
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorColes, Andrew
dc.contributor.authorGrigorenko, Anastasia
dc.contributor.authorVanjielli, Lorenc
dc.contributor.authorSousa, Jacquelyn
dc.contributor.authorMcHugh, Nicholas
dc.contributor.authorHassler, Matthew
dc.contributor.authorSantarelli, Francesco
dc.contributor.authorHeneka, Michael T
dc.contributor.authorRogaev, Evgeny I
dc.contributor.authorKhvorova, Anastasia
dc.date.accessioned2023-01-31T20:50:07Z
dc.date.available2023-01-31T20:50:07Z
dc.date.issued2022-07-02
dc.identifier.citationSilencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease Chantal M. Ferguson, Samuel Hildebrand, Bruno M.D.C Godinho, Julianna Buchwald, Dimas Echeverria, Andrew Coles, Anastasia Grigorenko, Lorenc Vanjielli, Jacquelyn Sousa, Nicholas McHugh, Matthew Hassler, Francesco Santarelli, Michael T. Heneka, Evgeny Rogaev, Anastasia Khvorova bioRxiv 2022.06.28.498012; doi: https://doi.org/10.1101/2022.06.28.498012en_US
dc.identifier.doi10.1101/2022.06.28.498012en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51614
dc.descriptionThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.en_US
dc.description.abstractThe most common genetic risk factor for late-onset Alzheimer’s disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function mechanisms. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to inhibit brain-specific ApoE with anti-sense oligonucleotides only modestly reduced ApoE expression and had no effect on amyloid burden in adult AD mice. Here, we optimized a divalent small interfering RNA (di-siRNA) to selectively and potently silence ApoE in the brain. Silencing brain ApoE in AD mice significantly reduced amyloid plaque formation without affecting systemic cholesterol levels, confirming that brain and liver APOE pools are spatially and functionally distinct. Mechanistically, APOE appears to be a scaffold for beta-amyloid aggregation that limits clearance by microglia. Di-siRNAs from this study can be taken to pre-clinical and clinical trials to accelerate development of AD-modifying therapies and establish siRNA-based modulation of ApoE as a viable path towards therapeutic development.en_US
dc.language.isoen_USen_US
dc.publisherCold Spring Harbor Laboratoryen_US
dc.relation.ispartofbioRxiven_US
dc.relation.urlhttps://doi.org/10.1101/2022.06.28.498012en_US
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.; Attribution-NoDerivatives 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nd/4.0/*
dc.subjectNeuroscienceen_US
dc.subjectAlzheimer’s diseaseen_US
dc.subjectgenetic risk factoren_US
dc.titleSilencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease [preprint]en_US
dc.typePreprinten_US
dc.source.journaltitlebioRxiv
refterms.dateFOA2023-01-31T20:50:08Z
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentPsychiatryen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.; Attribution-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.; Attribution-NoDerivatives 4.0 International