Silencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease [preprint]
Ferguson, Chantal M. ; Hildebrand, Samuel ; Godinho, Bruno M D C ; Buchwald, Julianna ; Echeverria, Dimas ; Coles, Andrew ; Grigorenko, Anastasia ; Vanjielli, Lorenc ; Sousa, Jacquelyn ; McHugh, Nicholas ... show 5 more
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Julianna Buchwald
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Abstract
The 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.
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Silencing 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/10.1101/2022.06.28.498012
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This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
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Now published in Alzheimer's & dementia : the journal of the Alzheimer's Association, https://doi.org/10.1002/alz.13703.