The findings, published in the Journal of Alzheimer’s Disease, could mark an early step toward developing cost-effective, pill-based alternatives to current antibody therapies, treatments that are expensive, complex to administer, and occasionally harmful. By targeting two specific receptors, SST1 and SST4, scientists may have opened a new avenue for fighting the most common cause of dementia.
Alzheimer’s disease, which affects millions worldwide, is characterized by the accumulation of toxic amyloid beta (Aβ) plaques in the brain. As these plaques build up, they interfere with communication between neurons and progressively erode memory and cognitive abilities. The main enzyme that clears Aβ is neprilysin, but its activity drops significantly with age and in patients with Alzheimer’s, reducing the brain’s natural capacity to fight the disease. That’s where this new receptor-based strategy comes in.
By focusing on somatostatin signaling, a system already known to affect neprilysin, scientists from the Karolinska Institutet and the RIKEN Center for Brain Science aimed to pinpoint exactly which receptors were responsible for neprilysin control. The results offer a compelling case for rethinking how future Alzheimer’s therapies might work.
Neprilysin Depends on SST1 and SST4 Receptors
Using genetically engineered mice lacking specific somatostatin receptors, the team found that neprilysin activity dropped significantly when both SST1 and SST4 were removed. According to the study, this dual receptor deficiency led to a clear decrease in neprilysin levels in a part of the hippocampus called the Lacunosum molecular layer, a region especially vulnerable to Alzheimer’s.
As a direct consequence of this receptor deletion, amyloid beta began to accumulate more heavily in the hippocampus, and the affected mice exhibited measurable memory impairments. Importantly, no such effects were observed in mice lacking only one of the receptors, underlining the redundant but essential role these two receptors play together.
The researchers also used ELISA to quantify neprilysin and Aβ levels, confirming that the absence of both receptors sharply increased Aβ42, the form most closely associated with plaque formation. “Our findings show that the brain’s own defense against amyloid beta can be strengthened by stimulating these receptors,” said Per Nilsson, one of the lead authors at Karolinska Institutet.
Drug Treatment Reverses aβ Buildup in Mouse Model
To test whether these receptors could be used therapeutically, the team administered CH275, a compound that selectively stimulates both SST1 and SST4, directly into the hippocampus of AppNL-G-F mice, a model genetically modified to mimic human Alzheimer’s. The treatment lasted four months and led to a noticeable increase in neprilysin levels alongside a reduced amyloid plaque load.
Behavioral changes were also recorded. In the Y-maze test, a standard method for assessing short-term memory in rodents, treated mice showed a trend toward improved cognitive performance. Meanwhile, results from the open field test suggested a significant reduction in anxiety levels, often heightened in Alzheimer’s models.
These effects were achieved without apparent toxicity, and concentration analysis confirmed that CH275 reached the hippocampus in sufficient quantities. According to data reported in the study, treated mice had nearly 2 μM of the compound in their brain tissue, enough to trigger the desired receptor activity.
Towards a Low-Cost Alternative to Antibody Therapies
Currently, the most advanced treatments for Alzheimer’s are based on monoclonal antibodies designed to remove Aβ from the brain. These therapies, while promising, come with high financial and logistical costs. They often require hospital-based infusion and carry a risk of side effects, including inflammation and bleeding in the brain.
Per Nilsson emphasized the appeal of a small-molecule approach, suggesting that drugs targeting SST1 and SST4 could eventually be taken as tablets. “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,” he noted.
Since SST1 and SST4 belong to the G protein-coupled receptor (GPCR) family, a class already well-explored in pharmacology, they present an accessible target for drug development. According to the Journal of Alzheimer’s Disease publication, this could lay the groundwork for future treatments that are both easier to manufacture and less invasive for patients.
As research continues, the discovery of these receptor “switches” offers a new perspective on how the brain regulates its own cleanup systems. And while these results are still limited to mice, they hint at a therapeutic strategy that might one day offer a more accessible and patient-friendly way to slow or prevent Alzheimer’s progression.