An "Amyloid-β Cleaner" for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction

Area of Science:

• Biomedical Engineering
• Neuroscience
• Materials Science

Background:

• Alzheimer's disease (AD) is marked by cognitive decline, driven by a detrimental cycle involving microglia and amyloid-beta (Aβ).
• Dysfunctional microglia exacerbate neuroinflammation and Aβ accumulation, accelerating AD progression.

Purpose of the Study:

• To develop and evaluate a zwitterionic poly(carboxybetaine) (PCB)-based nanoparticle (MCPZFS NP) for normalizing microglia and enhancing Aβ clearance in AD.
• To investigate the therapeutic efficacy of MCPZFS NPs compared to polyethylene glycol (PEG)-based nanoparticles (MEPZFS NPs).

Main Methods:

• Fabrication of PCB-based nanoparticles (MCPZFS NPs) and PEG-based nanoparticles (MEPZFS NPs).
• Assessment of microglial response, including proinflammatory mediator levels and Brain-Derived Neurotrophic Factor (BDNF) secretion.
• Evaluation of Aβ recruitment, phagocytosis, and degradation pathways (lysosomal/autophagy vs. proteasomal).
• In vivo studies using APPswe/PS1dE9 mouse model to assess Aβ burden, neuronal damage, memory, and neuroinflammation.

Main Results:

• MCPZFS NPs significantly reduced microglial priming and proinflammatory mediators while promoting BDNF secretion.
• Unlike PEG-based NPs, MCPZFS NPs effectively recruited Aβ into microglia, enhancing phagocytosis and shifting degradation to the proteasomal pathway.
• Treatment with MCPZFS NPs markedly attenuated Aβ burden, neuronal damage, memory deficits, and neuroinflammation in AD mice.

Conclusions:

• Zwitterionic PCB-based MCPZFS NPs show significant potential as an effective therapeutic agent for Alzheimer's disease.
• These nanoparticles act as an "Aβ cleaner" by modulating microglial function and enhancing Aβ clearance.
• The findings offer a novel therapeutic strategy for AD by targeting the microglia-Aβ vicious cycle.