Lipoprotein-Inspired Nanoscavenger for the Three-Pronged Modulation of Microglia-Derived Neuroinflammation in Alzheimer's Disease Therapy.

Abstract

The inflammatory dysfunction of microglia from excess amyloid-β peptide (Aβ) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and β-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood-brain barrier and sequentially target Aβ plaque, where Aβ catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aβ clearance with an antibody-like Aβ binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aβ production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the double-edged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.

• Authors: Huaqing Zhang, Wenxin Jiang, Yuanpei Zhao, Tingting Song, Yilong Xi, Guochen Han, Yi Jin, Mingjie Song, Kaiwen Bai, Jianping Zhou, Yang Ding
• Journal: Nano letters (Nano Lett) Vol. 22 Issue 6 Pg. 2450-2460 (03 23 2022) ISSN: 1530-6992 [Electronic] United States
• PMID: 35271279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoproteins, HDL
• Curcumin

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Animals
• Curcumin
• Disease Models, Animal
• Lipoproteins, HDL (metabolism)
• Mice
• Mice, Transgenic
• Microglia (metabolism)
• Neuroinflammatory Diseases