Researchers at Sweden’s Karolinska Institutet and Japan’s RIKEN Center for Brain Science report that two somatostatin receptors, SST1 and SST4, jointly regulate levels of neprilysin—an enzyme that breaks down amyloid-beta—in the hippocampus. In mouse models, activating the receptors raised neprilysin, reduced amyloid-beta buildup and improved memory-related behavior, the team said.
Alzheimer’s disease is the leading cause of dementia and is marked by the accumulation of amyloid-beta (Aβ) into plaques in the brain.
Scientists at Karolinska Institutet in Sweden and the RIKEN Center for Brain Science in Japan say they have identified two receptors—somatostatin receptors SST1 and SST4—that act together to regulate the brain enzyme neprilysin, which helps break down Aβ. The work was published in the Journal of Alzheimer’s Disease.
In experiments using genetically modified mice, the researchers found that when both receptors were missing, neprilysin levels fell and Aβ accumulated. The mice also showed memory problems in behavioral tests, the researchers reported.
The team also tested a compound designed to activate SST1 and SST4. In mice with Alzheimer’s-like brain changes, stimulating the receptors increased neprilysin levels, reduced Aβ buildup, and improved memory-related behavior. The researchers said the treatment did not cause serious side effects in the mice.
“Our findings show that the brain’s own defence against amyloid beta can be strengthened by stimulating these receptors,” said Per Nilsson, a docent at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society.
The researchers noted that many of the most advanced Alzheimer’s therapies currently rely on antibodies that target amyloid. They said such treatments can be expensive and may cause significant side effects in some patients.
“If we can instead develop small molecules that pass the blood-brain barrier, our hope is that we will be able to treat the disease at a significantly lower cost and without serious side effects,” Nilsson said.
SST1 and SST4 are part of the large family of G protein-coupled receptors (GPCRs), a class of proteins commonly targeted in drug development. The researchers said this could make it feasible to pursue pill-based treatments aimed at enhancing the brain’s own amyloid-clearing mechanisms.
According to the research summary, the project involved Karolinska Institutet, RIKEN, and other international universities, and was supported by funders that included the Swedish Research Council, the Hållsten Research Foundation, the Alzheimer’s Foundation, a private initiative described as “Innovative ways to fight Alzheimer´s disease — Leif Lundblad Family,” and RIKEN. The researchers reported no conflicts of interest.
