The bs-YHEDA peptide protects the brains of senile mice and thus recovers intelligence by reducing iron and free radicals.

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Iron accumulates in the brain with age and catalyzes free radical damage to neurons, thus playing a pathogenic role in Alzheimer's disease. To decrease the incidence of Alzheimer's disease, the authors synthesized the iron-affinitive peptide 5YHEDA to scavenge the excess iron in the senile brain: YHEDAYHEDAYHEDAYHEDAYHEDA.

However, the blood-brain barrier (a layer of cells around blood vessels in central nervous system) blocks the entrance of macromolecules into the brain, thus decreasing the therapeutic effects. Several receptors present in the BBB, including transferrin, the insulin receptor, and the low-density lipoprotein receptor (LDLR), are known to allow the passage of cognate protein ligands into the brain

To facilitate the entrance of the 5YHEDA peptide, the authors linked the low-density lipoprotein receptor-binding segment of ApoB-100 to 5YHEDA. Apolipoprotein B-100 (ApoB-100) is a lipid carrier. When recognized and bound by LDLR at the BBB, the complex can be converted to an endosome, subsequently resulting in transcytosis to the abluminal side of the BBB.

There, the apolipoprotein can be released for uptake by neurons and/or astrocytes when the pH is reduced, and the receptor is recycled to the cell surface.

Lipid-interactive regions and LDLR-binding regions are scattered in ApoB-100. The primary LDLR-binding region is located between amino acids 3359 and 3367, which consists of nine amino residues with the sequence “QSDIVAHLL”. To facilitate transport of the therapeutic YHEDA peptide across the BBB, the authors added the aforementioned LDLR-binding segment in ApoB-100 to the C-terminal of the synthesized therapeutic 5-YHEDA oligomer.


Using this method, they intended to deliver 5-YHEDA into the brains of senescent (SN) mice via LDLR-mediated endocytosis.

The SN Kunming mice exhibiting AD symptoms were divided into untreated, 5-YHEDA–treated, and bs-5- YHEDA–treated groups. Two hundred microliters of 20 mM 5-YHEDA or bs-5-YHEDA solution was intracardially injected into each mouse in the latter two groups weekly. The 6-month-old mice and the aging mice that did not display SN symptoms were used as the controls. Six weeks later, all mice underwent a 4-day MWM test after 1 day of adaptation. The path that the mouse swam to return to the underwater platform and the time spent were recorded to evaluate the individual’s cognitive ability

The results of intravenous injections of bs-5YHEDA into senescent mice demonstrated that bs-YHEDA entered the brain, increased ferriportin levels, reduced iron and free radical levels, decreased the consequences of neuronal necrosis and ameliorated cognitive disfunction without kidney or liver damage. bs-5YHEDA is a safe iron and free radical remover that potentially alleviates aging and Alzheimer's disease.

The bs-5-YHEDA–treated SN mice took only 57 seconds on average and swam 220 cm to return to the hidden platform in the MWM, nearly 25 seconds faster and 90 cm less than the untreated mice and the 5-YHEDA–treated SN mice , which suggests that the synthesized bs-5-YHEDA peptide prevented the deterioration of cognition and memory in the mice.

Read the original article on Pubmed

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