Restoring lysosomal homeostasis in microglia via a catch-and-patch nanomedicine for Alzheimer's disease

Lysosomal homeostasis acts as the tipping point at Aß deposition and clearance, critically dictating the trajectory of Alzheimer's disease (AD) pathology. While monoclonal antibodies have shown promise in reducing extracellular Aß burden, they inadvertently induce a massive Aß influx into microglia that overwhelms the lysosomal degradation capacity. The Aß overload results in toxic intracellular Aß spillover and increases the risk of inflammatory side effects. We show that the AMPK-TFEB axis is essential for maintaining microglial function by regulating lysosome activity and Aß clearance. Building on this insight, we develop a polymeric micelle capable of removing both extracellular and intracellular Aß while preserving intracerebral homeostasis. This nanomedicine facilitates microglial endocytosis of Aß deposits and stimulates TFEB-mediated lysosome biogenesis in a pH-responsive manner, thereby expanding the lysosomal capacity to manage the Aß influx. Through this “catch-and-patch” mechanism, it functions as an Aß scavenger and stabilizes microglial activity at a steady-state setpoint. Intravenous administration of the micelle significantly reduces Aß burden and mitigates cognitive decline in 5xFAD mice. Minimal cerebral amyloid angiopathy or inflammation is observed compared to anti-Aß antibody therapy. We provide a proof of principle for safe and effective AD treatment by synergistically targeting the extracellular-intracellular Aß cascade. Overall design: Hippocampus from 5xFAD mice treated with saline, Aducanumab, or ACLP-NT were collected and immediately immersed in RNA preservation solution for storage at -80°C. Total RNA was extracted from hippocampus using Trizol reagent, and mRNA sequencing was performed.