Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice

Abstract

Introduction Iron accumulates in the brain during aging, which catalyzes radical formation, causing neuronal impairment, and is thus considered a pathogenic factor in Alzheimer's disease (AD). To scavenge excess iron‐catalyzed radicals and thereby protect the brain and decrease the incidence of AD, we synthesized a soluble pro‐iron 5‐YHEDA peptide. However, the blood‐brain barrier (BBB) blocks large drug molecules from entering the brain and thus strongly reduces their therapeutic effects. However, alternative receptor‐ or transporter‐mediated approaches are possible. Methods A low‐density lipoprotein receptor (LDLR)‐binding segment of Apolipoprotein B‐100 was linked to the 5‐YHEDA peptide (bs‐5‐YHEDA) and intracardially injected into senescent (SN) mice that displayed symptoms of cognitive impairment similar to those of people with AD. Results We successfully delivered 5‐YHEDA across the BBB into the brains of the SN mice via vascular epithelium LDLR‐mediated endocytosis. The data showed that excess brain iron and radical‐induced neuronal necrosis were reduced after the bs‐5‐YHEDA treatment, together with cognitive amelioration in the SN mouse, and that the senescence‐associated ferritin and transferrin increase, anemia and inflammation reversed without kidney or liver injury. Discussion bs‐5‐YHEDA may be a mild and safe iron remover that can cross the BBB and enter the brain to relieve excessive iron‐ and radical‐induced cognitive disorders.

Comprehensive Analysis of Mouse Hippocampal Lysine Acetylome Mediated by Sea Cucumber Peptides Preventing Memory Impairment

“…Several receptor-mediated transport systems have been shown to be feasible to peptide delivery across the BBB (e.g., insulin, folate, transferrin, and lipoprotein) . Zou et al reported that a synthesized neuron-protective 5-YHEDA peptide with apolipoprotein B-100, a lipid carrier, was transferred to the brain through the BBB via a low-density lipoprotein receptor to reduce excess brain iron and radical-induced neuronal necrosis . These results revealed amino acid residues for acetylation sites and the conserved motif sequences, which could supplement the database with valuable information for acetylated protein in mouse hippocampus.…”

Epigenetics in Alzheimer’s Disease

“…HDAC inhibitors have been shown to reduce the amount of phosphorylated tau related to learning and memory in the brain and downregulate the aggregation of tau associated with neuronal apoptosis to improve cognitive dysfunction in mice ( Fan et al, 2018 ). Recent studies have found that a synthetic bs-5-YHEDA peptide ( Zou et al, 2019 ) decreased the methylation of H3 histone levels in the brains of senile mice but enhanced acetylation. Furthermore, by phosphorylating the transcription factor p-ETS1, the bs-5-YHEDA peptide reversed the transcription of SLC40A1 and upregulated ferriportin in the brains of senile mice, thus enhancing the excretion of iron accumulated in the aging brain and consequently protecting neurons and alleviating symptoms such as AD ( Figure 1 ).…”

Production of Bioactive Peptides from Sea Cucumber and Its Potential Health Benefits: A Comprehensive Review

“…Moreover, it should be determined whether SCP exerts its neuroprotective functions by influencing intestinal flora or the hippocampus by crossing the blood−brain barrier (BBB). 71,78 4.8. Micromineral-Chelating Peptides.…”

“…There is a need to develop appropriate approaches for screening and the identification of highly active peptide sequences and to establish structure–activity relationships. Moreover, it should be determined whether SCP exerts its neuroprotective functions by influencing intestinal flora or the hippocampus by crossing the blood–brain barrier (BBB). , …”