PT - JOURNAL ARTICLE AU - Suresh K Swaminathan AU - Andrew L Zhou AU - Kristen M Ahlschwede AU - Geoffry L Curran AU - Val J Lowe AU - Ling Li AU - Karunya K Kandimalla TI - HDL mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid beta distribution between brain and plasma AID - 10.1124/jpet.120.265876 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.120.265876 4099 - http://jpet.aspetjournals.org/content/early/2020/08/10/jpet.120.265876.short 4100 - http://jpet.aspetjournals.org/content/early/2020/08/10/jpet.120.265876.full AB - 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.SIGNIFICANCE STATEMENT The brain permeability of the ApoA-I mimetic peptide 4F was estimated to be ~1000 fold greater than ApoA-I after systemic injection of radiolabeled peptide/protein in mice. Further, 4F treatment increased the brain efflux of amyloid beta and also decreased its brain influx, as evaluated in mice and in BBB cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer's disease.