High-Density Lipoprotein Mimetic Peptide 4F Efficiently Crosses the Blood-Brain Barrier and Modulates Amyloid-βDistribution between Brain and Plasma
| Autor: | Kristen M. Ahlschwede, Geoffry L. Curran, Karunya K. Kandimalla, Val J. Lowe, Ling Li, Suresh Kumar Swaminathan, Andrew L Zhou |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Blood–brain barrier Metabolism Transport and Pharmacogenomics Mice 03 medical and health sciences 0302 clinical medicine In vivo Internal medicine medicine Animals Cognitive decline Pharmacology Amyloid beta-Peptides Chemistry medicine.disease Peptide Fragments Endothelial stem cell Protein Transport 030104 developmental biology medicine.anatomical_structure Endocrinology Transcytosis Blood-Brain Barrier Molecular Medicine Cerebral amyloid angiopathy Alzheimer's disease Peptides 030217 neurology & neurosurgery Lipoprotein |
| Zdroj: | J Pharmacol Exp Ther |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 [(125)I]Aβ trafficking from brain to blood and from blood to brain. After systemic injection in mice, the BBB permeability of [(125)I]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 [(125)I]4F were ∼1000-fold higher compared with those determined for [(125)I]ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected [(125)I]Aβ42. Conversely, 4F infusion decreased the brain influx of systemically injected [(125)I]Aβ42. Interestingly, 4F did not significantly alter the brain influx of [(125)I]Aβ40. To corroborate the in vivo findings, we evaluated the effects of 4F on [(125)I]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 [(125)I]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. |
| Databáze: | OpenAIRE |
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