A Self-Reinforced "Microglia Energy Modulator" for Synergistic Amyloid-β Clearance in Alzheimer's Disease Model

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• Microglial phagocytosis is crucial for clearing amyloid-β (Aβ) in Alzheimer's disease (AD), but is impaired by defective microglial metabolism.
• Existing treatments face challenges in effectively targeting microglial dysfunction and Aβ clearance.

Purpose of the Study:

• To develop a novel therapeutic strategy, LND@HMPB-T7, to enhance microglial energy metabolism for improved Aβ clearance in AD.
• To evaluate the efficacy and safety of LND@HMPB-T7 in preclinical AD models.

Main Methods:

• Conjugation of lonidamine (LND) with hollow mesoporous Prussian blue (HMPB) and modification with a T7 peptide for brain penetration.
• Assessment of LND@HMPB-T7's impact on microglial ATP production, Aβ phagocytosis, and mitochondrial function.
• In vivo studies in AD mice to evaluate therapeutic effects on Aβ burden, neuroinflammation, and cognitive deficits.

Main Results:

• LND@HMPB-T7 effectively delivered to the AD brain, stimulating microglial ATP production to fuel Aβ phagocytosis.
• The nanozyme component (HMPB) mitigated LND-induced mitochondrial side effects, further enhancing ATP production and Aβ clearance.
• In vivo studies demonstrated synergistic Aβ clearance, reduced neuroinflammation, and improved cognitive function in AD mice.

Conclusions:

• LND@HMPB-T7 acts as a microglial energy modulator, offering a safe and effective approach for synergistic Aβ clearance.
• Repurposed drug LND@HMPB-T7 shows significant potential for clinical application in treating Alzheimer's disease.