Scientists searching for a way to prevent Alzheimer's disease made an unexpected discovery: a compound they had developed in the laboratory was already present naturally in the human body. The Russia-based researchers also found that levels of the molecule were significantly lower in people diagnosed with Alzheimer's disease than in healthy volunteers. The discovery has prompted researchers to investigate whether HAEE, a naturally occurring peptide, could serve as both a biomarker and a potential treatment for Alzheimer's disease.
The study was published in PNAS Nexus on October 20. "The discovery of endogenous HAEE has radically shifted the focus of my research," one study author, Dr. Sergey Kozin, a scientist at the Engelhardt Institute of Molecular Biology at the Russian Academy of Sciences, told Newsweek.
"While I previously viewed HAEE solely as an effective treatment for Alzheimer’s disease, it has now become clear to me that endogenous HAEE plays a multifaceted role in regulating the nervous system," he said. He added that he believes uncovering the molecular mechanisms of how HAEE influences biological processes is "an exciting and highly promising endeavor." It is currently understood that accumulation of proteins amyloid-beta and tau is one of the factors that results in Alzheimer's disease development, alongside inflammation, as well as vascular and metabolic changes. Amyloid-beta is thought to build up outside the nerve cells, into plaques, and this is thought to disrupt communication between brain cells and eventually contribute to their death.
It is the death of these vital cells, which are responsible for storing, processing and retrieving information, that is thought to lead to Alzheimer's. Researchers also believe this amyloid-beta accumulation could trigger tau tangles, which is a buildup of the tau protein, to spread throughout the brain, although the role and interaction of these proteins is still not completely understood. As the researchers sought to find a treatment for Alzheimer's disease, they looked at how they could disrupt non-typical interactions between amyloid-beta protein and zinc ions, as they believed this interaction could be fundamental to the development of plaques in the brain.
In 2015, they found the peptide Ac-His-Ala-Glu-Glu-NH2 (known as HAEE), which they had synthetically engineered, could interfere with the growth of amyloid-beta in mice. These findings were published in the Journal of Alzheimer's Disease, Kozin said. What they noticed was that "the HAEE peptide and the amyloid-beta molecule form a highly stable intermolecular complex that cannot aggregate, either in the blood or in brain tissue," he said.
Then, in 2021, as they prepared for clinical trials, Kozin said the team developed a method to "quantify HAEE concentrations in biological samples, intending to use it to assess the peptide’s pharmacokinetic properties." While analysing blood plasma samples from 150 participants without a diagnosis of cognitive impairment, researchers discovered, to their "utter astonishment," that HAEE occurs naturally in human blood, Kozin said. He added that it "seemed inconceivable... that a molecule we had engineered would turn out to be a natural component of the human body." He said: "This discovery was profound, immediately suggesting that synthetic HAEE could be an ideal treatment for Alzheimer’s disease—after all, unlike any other known anti-amyloid drug candidate, it is a naturally occurring substance." The researchers also note in their study that to their "best knowledge," this was "the first time that an artificially created tetrapeptide has been found to be an endogenous component in the human body." The team also found that those who had received a diagnosis of Alzheimer's had significantly reduced levels (almost a twofold reduction) of the HAEE peptide. This association was identified across a sample of 200 participants with a clinical diagnosis of Alzheimer's and a sample of 150 participants without cognitive impairment.
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