Extracellular matrix remodeling enhancing astrocyte lysosome pathway to reverse memory defected in Alzheimer’s disease

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer’s disease (AD) risk, but its functions are not fully understood. Here, we found that medial prefrontal cortex (mPFC) injection with chondroitinase ABC (ChABC) to remodel ECM reverses short-term memory loss and reduces Aβ deposition in 5xFAD mice. ECM remodeling also reactivates astrocytes, untangles aggrecan’s entanglement with amyloid-beta (Aβ) plaques, and encourages astrocyte recruitment to the surrounding plaques. ECM remodeling promotes astrocyte phagocytosis of Aβ plaque by activating the astrocyte phagocytosis receptor mertk and astrocytic vesicle circulation. Importantly, ECM remodeling enhances the autophagy-lysosome pathway in astrocytes to mediate Aβ clearance and alleviate AD pathology. Our work thus discovers a cellular mechanism to remodel the ECM to active astrocyte autophagic lysosomal pathway alleviation AD pathology. It may represent a potential therapeutic strategy and serve as a hallmark for treating AD.