Abstract
Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid - β (A β) 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]A β 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]A β42. Conversely, 4F infusion decreased the brain influx of systemically injected [ 125I]A β42. Interestingly, 4F did not significantly alter the brain influx of [ 125I]A β40. To corroborate the in vivo findings, we evaluated the effects of 4F on [ 125I]A β42 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]A β42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled A β42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain A β 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.
Original language | English (US) |
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Pages (from-to) | 308-316 |
Number of pages | 9 |
Journal | Journal of Pharmacology and Experimental Therapeutics |
Volume | 375 |
Issue number | 2 |
DOIs | |
State | Published - Nov 1 2020 |
Bibliographical note
Publisher Copyright:Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
Keywords
- Amyloid beta-Peptides/blood
- Animals
- Blood-Brain Barrier/metabolism
- Mice
- Peptide Fragments/blood
- Peptides/metabolism
- Protein Transport/drug effects
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural