High-density lipoprotein mimetic peptide 4F efficiently crosses the blood-brain barrier and modulates amyloid-β distribution between brain and plasma

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]Ab 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 x 10²⁶ 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]Ab42. Conversely, 4F infusion decreased the brain influx of systemically injected [¹²⁵I]Ab42. Interestingly, 4F did not significantly alter the brain influx of [¹²⁵I]Ab40. To corroborate the in vivo findings, we evaluated the effects of 4F on [¹²⁵I]Ab42 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]Ab42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Ab42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain Ab 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 -b 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.