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Research ArticleMetabolism, Transport, and Pharmacogenomics

High-Density Lipoprotein Mimetic Peptide 4F Efficiently Crosses the Blood-Brain Barrier and Modulates Amyloid-β Distribution between Brain and Plasma

Suresh K. Swaminathan, Andrew L. Zhou, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe, Ling Li and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics November 2020, 375 (2) 308-316; DOI: https://doi.org/10.1124/jpet.120.265876
Suresh K. Swaminathan
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Andrew L. Zhou
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Kristen M. Ahlschwede
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Geoffry L. Curran
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Val J. Lowe
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Ling Li
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Karunya K. Kandimalla
Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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Abstract

Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid -β (Aβ) deposition and mitigated cognitive decline in Alzheimer 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 examined the BBB permeability of 4F and its effects on [125I]Aβ trafficking from brain to blood and 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 × 10−6 ml/g per second in various brain regions. The PS products of [125I]4F were ∼1000-fold higher compared with those determined for [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 systemically injected [125I]Aβ42. Interestingly, 4F did not significantly alter the brain influx of [125I]Aβ40. To corroborate the in vivo findings, we evaluated 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 Aβ burden reported in AD mice after oral 4F administration, which represents a novel strategy for treating AD and cerebral amyloid angiopathy.

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 -β and also decreased its brain influx, as evaluated in mice and in blood-brain barrier cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer disease.

Footnotes

    • Received March 3, 2020.
    • Accepted July 24, 2020.
  • ↵1 S.K.S. and A.L.Z. contributed equally to this work.

  • This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [Grant RF1-00056030] and by National Institutes of Health National Institute on Aging [Grant RF1-AG058081] and [Grant R21-AG056025].

  • https://doi.org/10.1124/jpet.120.265876.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
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Research ArticleMetabolism, Transport, and Pharmacogenomics

HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma

Suresh K. Swaminathan, Andrew L. Zhou, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe, Ling Li and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 308-316; DOI: https://doi.org/10.1124/jpet.120.265876

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Research ArticleMetabolism, Transport, and Pharmacogenomics

HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma

Suresh K. Swaminathan, Andrew L. Zhou, Kristen M. Ahlschwede, Geoffry L. Curran, Val J. Lowe, Ling Li and Karunya K. Kandimalla
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 308-316; DOI: https://doi.org/10.1124/jpet.120.265876
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