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."
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How Alzheimer's Disease Could Develop
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.
The Surprising Discovery
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.
"Our confidence in the therapeutic potential of synthetic HAEE grew even further when we subsequently discovered that patients with Alzheimer’s disease exhibit a significant deficiency in endogenous HAEE," Kozin said.
"I am confident that compensating for the deficiency of endogenous HAEE, which we observe in patients with Alzheimer’s disease, through subcutaneous or intranasal administration of a synthetic HAEE peptide will, at the very least, halt the progression of the disease," he said.
What This Means For Alzheimer's
Dr. Ottavio Arancio, a professor of pathology, cell biology and medicine at Columbia University, told Newsweek that this is "a fascinating result," but he added that because "it’s such an unusual claim, the identification is worth nailing down carefully and confirming independently, since their method pins down most of the molecule but not quite all of it."
"The other open question is how the body would produce it," he said. "The authors raise this themselves and suggest there may be a mechanism still to be discovered, which would be interesting in its own right if it turns out to be the case."
He also said he'd be curious to understand why the peptide levels "weren’t lower in people with more advanced disease. If a shortage of this molecule were driving Alzheimer’s, you might expect the sickest patients to have the least of it."
Arancio said this could have several explanations, but one "worth ruling out is simply how the two sets of blood samples were collected and handled," as "with fragile molecules like this, small differences in handling can affect the result."
The scientist said that next, they need to confirm "exactly which molecule they’re seeing," and report "how the two groups’ blood samples were handled."
He said: "I’d like to see it survive those tests, because a new molecule in human biology would be real news."
Chuanhai Cao, a professor of pharmaceutical sciences at the University of South Florida, told Newsweek that "this discovery further supports the view that amyloid-beta aggregation may be a causative factor in Alzheimer’s disease, and that safely and effectively removing aggregated amyloid-beta or preventing its aggregation in the first place remains a viable approach to treatment and prevention."
He said that "many therapeutic development efforts focus solely on the disease-associated pathological proteins, such as aggregated amyloid-beta or hyperphosphorylated tau in the brain, without treating the body as a closed biological system, and in particular without accounting for age-related factors."
Cao added: "As a result, these treatments may cause unavoidable adverse effects in patients whose immunity is already compromised. I believe the best approach to Alzheimer’s disease must address pathological protein and strengthen immunity at the same time."
Reference
Arthur T Kopylov, Ruslan Yu Yakovlev, Aleksei V Trukhin, Yuri M Poluektov, Anastasia A Anashkina, Sergey A Kozin, (2026) Beyond Alzheimer’s story: How an engineered molecule gained an endogenous essence, PNAS Nexus. https://doi.org/10.1093/pnasnexus/pgag320