Biomimetic silibinin-loaded macrophage-derived exosomes induce dual inhibition of Aß aggregation and astrocyte activation to alleviate cognitive impairment in a model of Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease of the central nervous system. Due to its complex pathogenesis and the difficulty of drugs to cross the blood brain barrier (BBB), no effective clinical drugs are currently available that prevent the development of the course of AD. Silibinin (Slb) is known to exert dual therapeutic effects on reducing amyloid-ß (Aß) aggregation and deactivating astrocytes to improve behaviour and cognitive performance in subjects with Alzheimer's disease (AD). However, the poor brain targeting ability and low bioavailability limit its wide application. We aimed to encapsulate Slb in macrophage-derived exosomes (Exo-Slb) to improve its brain targeting ability. After entering the brain, exosomal Slb selectively interacted with Aß monomers to reduce its aggregation. At the same time, Exo-Slb was internalized in astrocytes to inhibit their activation and alleviate astrocyte inflammation-mediated neuronal damage. Finally, Exo-Slb potently ameliorated cognitive deficits in AD mice.

Brain Microvascular Endothelial Cell Derived Exosomes Potently Ameliorate Cognitive Dysfunction by Enhancing the Clearance of Aß Through Up-Regulation of P-gp in Mouse Model of AD.

Accumulation of amyloid-ß (Aß) peptides in the brain is regarded as a major contributor to the pathogenesis and progression of Alzheimer's disease (AD). P-glycoprotein (P-gp) as a member of ABC transporter family situated in blood brain barrier (BBB) plays a role on cleaning of Aß via its efflux transport effect in the treatment of AD. However, the expression of P-gp in pathological BBB was lower than that in normal BBB, thus impeding the clearance of Aß. Here, we used human brain microvascular endothelial cells (HBMVECs) derived exosomes (HBMVECs-Ex) inheriting P-gp as an extracorporeal Aß cleansing system to remove Aß peptides from the brain by specific capture between P-gp and Aß. The results showed that HBMVECs-Ex inheriting P-gp greatly facilitated the cerebral clearance of Aß by effectively transporting Aß out of brain and potently ameliorated cognitive dysfunction in AD mice. Taken together, HBMVECs-Ex provided a new strategy on the treatment of AD.