Abstract

Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid beta (Aβ) deposition and mitigated cognitive decline in Alzheimer's disease (AD) transgenic mice. Since the major protein component of HDL particles, apolipoprotein A-I (ApoA-I), has very low permeability at the blood-brain barrier (BBB), we investigated 4F, an 18 amino acid ApoA-I/HDL mimetic peptide, as a therapeutic alternative. Specifically, we investigated the BBB permeability of 4F and its effect on ¹²⁵I-Aβ trafficking from brain-to-blood and also from blood-to-brain. After systemic injection in mice, the BBB permeability of ¹²⁵I-4F, estimated as the permeability-surface area (PS) product, ranged between 2 and 5 x 10-6 ml/g/s in various brain regions, which represents a ~1000 fold increase in permeability compared to ¹²⁵I-ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected ¹²⁵I-Aβ42. Conversely, 4F infusion decreased the brain influx of ¹²⁵I-Aβ42. Interestingly, 4F did not significantly alter the brain influx of ¹²⁵I-Aβ40. To corroborate the in vivo findings, we investigated the effects of 4F on ¹²⁵I-Aβ42 transcytosis across polarized human BBB endothelial cell (hCMEC/D3) monolayers. Treatment with 4F increased the abluminal-to-luminal flux and decreased the luminal-to-abluminal flux of ¹²⁵I-Aβ42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Aβ42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain amyloid burden reported in AD mice after oral 4F administration, which represents a novel anti-amyloid strategy for treating AD patients.