Scientists in Sweden and Japan have identified two "brain switches" that, when activated, boost a natural enzyme called neprilysin, clear amyloid plaques, and improve memory in mice with Alzheimer's‑like changes.
Researchers at Karolinska Institutet and the RIKEN Center for Brain Science report that two somatostatin receptors, known as SST1 and SST4, work together to control how much neprilysin is available in the hippocampus, a key memory center in the brain. Neprilysin plays a major role in breaking down amyloid beta, the protein that clumps into sticky plaques in Alzheimer's disease.
How the New Brain "Switches" Work
In aging and Alzheimer's, neprilysin activity falls, which allows amyloid beta to build up. The new study suggests that directly turning on SST1 and SST4 could restore this natural cleaning system and offer a new way to treat the disease.
Alzheimer's disease is the leading cause of dementia worldwide and is defined in part by the slow buildup of amyloid beta plaques between nerve cells, according to Science Daily.
Current approved drugs that target amyloid are mostly antibody‑based infusions, which can be very expensive and may cause side effects such as brain swelling or bleeding in some patients. In contrast, SST1 and SST4 belong to the G protein‑coupled receptor (GPCR) family, a class of proteins that many existing oral medicines already target.
Because of this, the team believes it may be possible to design small‑molecule pills that act on these receptors, cross the blood–brain barrier, and be cheaper and safer than antibody therapies.
Evidence from Mouse Experiments
To uncover how these receptors control amyloid clearance, the scientists used several mouse lines and cell models. They created double knockout mice that lack both SST1 and SST4 and then examined neprilysin levels and amyloid beta in the hippocampus.
In these animals, neprilysin in specific presynaptic regions dropped, amyloid beta accumulated more, and the mice showed memory‑related problems in behavioral tests, linking the loss of these receptors to worse brain function.
The team then moved to a proof‑of‑concept treatment approach. In mice genetically engineered to develop Alzheimer's‑like pathology, they tested a compound that activates both SST1 and SST4.
After treatment, neprilysin levels rose, amyloid beta deposits decreased, and the animals performed better on tasks that depend on memory. According to the researchers, these benefits appeared without serious side effects, making the receptors attractive drug targets, Medical Xpress reported.
What This Could Mean for Future Treatments
The findings also help answer a long‑standing question in Alzheimer's research: which somatostatin receptors are responsible for controlling neprilysin in the brain. Earlier work had shown that somatostatin, a signaling peptide, can increase neprilysin activity and promote amyloid breakdown, but the specific receptor subtypes involved were unclear.
By combining in vitro neuron cultures, receptor‑specific agonists, and multiple knockout models, the new study shows that SST1 and SST4 jointly regulate neprilysin in a "redundant" way, meaning that loss of both is needed to see a strong effect.
Scientists stress that the work is still at the preclinical stage and has only been demonstrated in mice and cell systems. Human brains are more complex, and many experimental Alzheimer's treatments that seemed promising in animals have not worked in clinical trials.
However, because GPCR‑targeting drugs are common in other diseases, the pathway from this discovery to potential human testing may be more straightforward than for entirely new types of therapies.
Future studies will need to refine SST1/SST4‑selective compounds, test long‑term safety, and confirm that boosting neprilysin through these receptors can meaningfully slow or prevent cognitive decline in people.
The research involved an international team from Karolinska Institutet, RIKEN Center for Brain Science, and other universities, and was published in the Journal of Alzheimer's Disease.
The authors suggest that enhancing the brain's own waste‑clearing systems, rather than only adding external antibodies, could become a central strategy in future Alzheimer's treatments, as per Sci Tech Daily.
