(692j) Brain-Inspired Lipoprotein Particles to Restore Lipid Transport in the Alzheimer’s Disease Brain

Lipid transport within the brain is essential for maintaining healthy neuronal function. This process occurs largely via lipoprotein particles synthesized by glial cells, primarily astrocytes, and delivered to neurons to support their high metabolic and structural demands. Disruption of this system is a hallmark of neurodegenerative diseases, including Alzheimer’s disease (AD). Of note, APOE is the strongest genetic risk factor for sporadic AD and encodes ApoE, the predominant protein found in brain lipoprotein particles. These endogenous nanoparticles in the cerebrospinal fluid (CSF) are separated from those of the periphery, such as HDL and LDL in the blood, and are distinguished by unique protein and lipid compositions. The high AD-risk ApoE4 protein variant exhibits reduced lipid transport efficiency, leading to lipid imbalances that exacerbate AD pathology.

In this work, we developed biomimetic nanoparticles inspired by brain lipoprotein particles to address lipid dysregulation in AD. Recently, we investigated how major risk factors for sporadic AD—APOE4 status, aging, and female chromosomal sex—led to lipidomic changes in the brain, CSF, and blood. Using mass spectrometry-based lipidomics on a mouse model with humanized APOE variants and two postmortem human cohorts, we identified a disrupted lipid economy in AD and APOE4 carriers: intracellular lipid accumulation in the brain coincided with reduced lipid transport in the CSF, impairing the buffering capacity required to maintain lipid homeostasis during aging and disease. To counteract these imbalances, we engineered reconstituted lipoprotein particles (rLPs) that mimic the structure and function of endogenous brain lipoproteins. These rLPs were designed, formulated, and characterized by methods including absorbance, dynamic light scattering, zeta potential analysis, and electron microscopy, demonstrating discoidal morphology optimal for lipid efflux capacity and diameters of approximately 10–30 nm depending on the formulation. Functional testing with human induced pluripotent stem cell (iPSC)-derived APOE4 astrocytes revealed that rLPs containing ApoE3 (non-risk form) enhanced lipid efflux and reduced intracellular lipid droplets by up to 90%. In vivo studies in an Alzheimer’s mouse model further highlighted the translational potential of this approach.

This work represents a biomimetic strategy for addressing lipid dysregulation in the brain, with broad implications for neurodegenerative disease therapy. By restoring lipid transport and homeostasis, synthetic rLPs could offer an approach to reduce AD risk and develop precision medicine interventions for brain health.