Silencing Apoe with divalent‐siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease
0301 basic medicine
Amyloid
Amyloid beta-Peptides
Apolipoprotein E4
neurodegeneration
oligonucleotide therapeutics
Brain
Amyloidogenic Proteins
Mice, Transgenic
Alzheimer's Disease
Mice
03 medical and health sciences
Apolipoproteins E
Alzheimer Disease
RNAi
siRNA
Animals
RNA, Small Interfering
Research Articles
Apoe
DOI:
10.1002/alz.13703
Publication Date:
2024-02-20T11:26:14Z
AUTHORS (15)
ABSTRACT
AbstractINTRODUCTIONThe most significant genetic risk factor for late‐onset Alzheimer's disease (AD) is APOE4, with evidence for gain‐ and loss‐of‐function mechanisms. A clinical need remains for therapeutically relevant tools that potently modulate APOE expression.METHODSWe optimized small interfering RNAs (di‐siRNA, GalNAc) to potently silence brain or liver Apoe and evaluated the impact of each pool of Apoe on pathology.RESULTSIn adult 5xFAD mice, siRNAs targeting CNS Apoe efficiently silenced Apoe expression and reduced amyloid burden without affecting systemic cholesterol, confirming that potent silencing of brain Apoe is sufficient to slow disease progression. Mechanistically, silencing Apoe reduced APOE‐rich amyloid cores and activated immune system responses.DISCUSSIONThese results establish siRNA‐based modulation of Apoe as a viable therapeutic approach, highlight immune activation as a key pathway affected by Apoe modulation, and provide the technology to further evaluate the impact of APOE silencing on neurodegeneration.
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