Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease...

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Autophagy, including macroautophagy and chaperone-mediated autophagy (CMA), is dysregulated in Alzheimer's disease (AD).
• Impaired autophagy contributes to the accumulation of toxic protein aggregates in AD.
• The blood-brain barrier (BBB) limits therapeutic strategies targeting autophagy in the brain.

Purpose of the Study:

• To investigate the role of dual autophagy pathway impairment in AD pathogenesis.
• To develop a novel drug delivery system for simultaneous activation of macroautophagy and CMA across the BBB.
• To evaluate the therapeutic efficacy of this dual-activation strategy in AD mouse models.

Main Methods:

• Development of Microglia-Liposome Fusion Extrusion (MiLi-FE) to create microglia-derived nanovesicles (AR@ENV).
• Codelivery of AR7 (CMA inducer) and rapamycin (macroautophagy inducer) via AR@ENV.
• Assessment of AR@ENV's BBB penetration, neuronal uptake, and therapeutic effects in AD mouse models.

Main Results:

• AR@ENV effectively crosses the BBB and targets AD brain pathology.
• Synchronous activation of CMA and macroautophagy by AR@ENV enhances clearance of β-amyloid and toxic aggregates.
• The treatment restores proteostasis, reduces neuroinflammation, and rescues cognitive deficits in AD mice.
• The MiLi-FE platform demonstrates versatility for CNS drug delivery.

Conclusions:

• Targeted, dual activation of autophagy pathways via AR@ENV is a promising therapeutic strategy for AD.
• The MiLi-FE platform offers a scalable approach for treating neurological disorders by enabling CNS drug delivery.
• This approach addresses the limitations of BBB penetration for autophagy-modulating therapies.