Regulating inflammation in Alzheimer's disease using a nanocleaner

In this new article publication from Acta Pharmaceutica Sinica B, authors Ting Lei, Zhihang Yang, Xue Xia, Yuxiu Chen, Xiaotong Yang, Rou Xie, Fan Tong, Xiaolin Wang, Huile Gao from Sichuan University, Chengdu, China and Macau University of Science and Technology, Macau, China discuss how nanocleaners can specifically penetrate the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease.

Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment ofAlzheimer's disease(AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβdeposition or TAU protein need to be resolved urgently.

The authors of this paper designed a nanocleaner with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote thetranscytosisof nanocleaner from endothelial cells into brain parenchyma.

Then exposed KLVFF can capture and carry Aβto microglia, attenuating Aβ-inducedneurotoxicity. Rapamycin, an autophagy promoter, is rapidly liberated from the nanocleaner in the high ROS level of lesions to improve Aβdegradation and normalize inflammatory condition. This design altogether accelerates Aβdegradation and alleviates oxidative stress and excessive inflammatory response.

Collectively, the findings of this paper offer a strategy to target AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy.