Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer's disease in a mouse model

Blood-brain barrier (BBB) dysfunction is an early pathological hallmark of Alzheimer’s disease (AD), occurring prior to amyloid-β (Aβ) accumulation. A key factor contributing to BBB damage in AD is the loss of endothelial expression of low-density lipoprotein receptor-related protein 1 (LRP1). Endothelial LRP1 is crucial for maintaining BBB integrity and facilitating the transcytosis of Aβ across the BBB for peripheral clearance. However, LRP1 is also expressed in other neural cell types, such as neurons, where it paradoxically promotes Aβ generation and tau propagation. These dual roles of LRP1 for different cell types present a challenge for developing effective AD therapy targeting LRP1. Simvastatin (SIM), an HMG-CoA reductase inhibitor, has been shown to induce compensatory upregulation of LRP1 expression. To harness this potential, we designed SIM-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) that can be effectively internalized by endothelial cells. Our findings demonstrate that intravenous (IV) injection with S@A-NPs upregulates endothelial LRP1 expression level, repairs BBB damage, attenuates Aβ accumulation, mitigates neurodegeneration, and ultimately preserves cognitive function in APP/PS1 mice. These results highlight the potential of endothelial delivery of SIM via nanoparticles to attenuate AD pathogenesis. Our study proposes a novel therapeutic strategy for AD by leveraging nanoparticle-mediated drug delivery. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01840-5.