Peptide-Functionalized Hydroxypropyl Cellulose Mitigates Amyloid-β Protein Induced Endothelial Leakiness and Enhances Cognitive Function in Alzheimer's Disease.

Amyloid-β (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis by inducing endothelial leakiness and disrupting blood-brain barrier (BBB) integrity via direct binding to endothelial tight junction proteins. In this work, a peptide-functionalized cellulose derivative (HPC-pet) was synthesized by conjugating hydroxypropyl cellulose (HPC) with the Aβ-targeting KLVFFAED peptide (pet). Integrative experimental and theoretical investigations were performed to characterize the efficacy and underlying mechanism of HPC-pet in mitigating amyloid - β protein-induced endothelial leakage (APEL), as well as to profile its pharmacokinetic behavior. Benefiting from the synergistic effects between HPC matrix and pet moieties, HPC-pet is capable of suppressing Aβ aggregation progression and encapsulating formed Aβ oligomers. In vitro cellular assays suggested that HPC-pet interferes with the binding of Aβ to endothelial junction proteins and mitigates APEL. Computational modeling further analyzed the intermolecular binding patterns among Aβ, HPC, and VE-cadherin to elucidate the molecular interaction mechanism. Consistent with in vitro and computational results, HPC-pet can efficiently traverse the BBB and mitigate APEL. Following sustained in vivo delivery of HPC-pet to AD mice, reduced cerebral Aβ plaque burden and improved cognitive function were detected. This strategy safeguards endothelial function from Aβ oligomer-mediated damage, offering a promising candidate for intervening Aβ-driven AD progression.