Dynamic Covalent Peptide-Drug Conjugates Address the Heterogeneity in Alzheimer's Disease Progression

Area of Science:

• Neuroscience
• Biomedical Engineering
• Pharmacology

Background:

• Alzheimer's disease (AD) progression is heterogeneous, complicating treatment efficacy.
• Current therapeutic strategies struggle with personalized dosing due to disease variability.

Purpose of the Study:

• To develop a hierarchical-responsive therapeutic agent (CPKNAs) that dynamically tracks AD progression biomarkers.
• To enable self-adaptive drug distribution and dosing tailored to individual AD phenotypes.

Main Methods:

• Self-assembly of phenylboronate ester-linked KLVFF peptide-curcumin conjugates (CPKNAs).
• Utilizing dynamic covalent bonds responsive to amyloid-β, reactive oxygen species, and glucose levels.
• In vitro testing across seven cellular models and in vivo testing using three transgenic mouse models of AD.

Main Results:

• CPKNAs demonstrated dynamic tracking of AD progression biomarkers.
• The agent achieved self-adaptive regulation of drug delivery based on disease stage.
• Consistent therapeutic outcomes were observed in mitigating cellular damage and improving brain dysfunction across models.

Conclusions:

• CPKNAs offer a promising adaptive therapeutic strategy for Alzheimer's disease.
• This approach effectively minimizes under- or overtreatment by tailoring interventions to specific AD phenotypes.
• The developed agent holds potential for more consistent and effective management of Alzheimer's disease.