Silencing Apoe with divalent‐siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease
Apolipoprotein E
Amyloid (mycology)
DOI:
10.1002/alz.13703
Publication Date:
2024-02-20T11:26:14Z
AUTHORS (15)
ABSTRACT
Abstract INTRODUCTION The most significant genetic risk factor for late‐onset Alzheimer's disease (AD) is APOE4 , with evidence gain‐ and loss‐of‐function mechanisms. A clinical need remains therapeutically relevant tools that potently modulate APOE expression. METHODS We optimized small interfering RNAs (di‐siRNA, GalNAc) to silence brain or liver Apoe evaluated the impact of each pool on pathology. RESULTS In adult 5xFAD mice, siRNAs targeting CNS efficiently silenced expression reduced amyloid burden without affecting systemic cholesterol, confirming potent silencing sufficient slow progression. Mechanistically, APOE‐rich cores activated immune system responses. DISCUSSION These results establish siRNA‐based modulation as a viable therapeutic approach, highlight activation key pathway affected by modulation, provide technology further evaluate neurodegeneration.
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