Researchers have identified two specific brain receptors that act as “switches” to control the breakdown of amyloid beta, the toxic protein responsible for forming sticky plaques in the brains of Alzheimer’s patients. This groundbreaking discovery, announced by scientists at Karolinska Institutet in Sweden and the RIKEN Center for Brain Science in Japan, suggests that the brain’s natural defense systems can be activated to fight the disease. The findings could pave the way for safer, more affordable pill-based treatments that avoid the high costs and side effects associated with current antibody therapies.
The study, published in the Journal of Alzheimer’s Disease, focuses on two G protein-coupled receptors known as SST1 and SST4. When activated, these receptors trigger the release of an enzyme called neprilysin, which breaks down amyloid beta. This mechanism offers a potential alternative to today’s dominant treatments, which typically rely on infused antibodies to target plaques directly.
Boosting the Brain’s Natural Defenses
The research team conducted their experiments using genetically modified mice and laboratory cell cultures to understand how these receptors influence Alzheimer’s pathology. They discovered that when the SST1 and SST4 receptors were missing or blocked, levels of the neprilysin enzyme dropped significantly. This reduction impaired the brain’s ability to degrade amyloid beta, leading to increased plaque accumulation and memory problems in the mice.
Conversely, when the researchers administered a compound designed to stimulate these specific receptors, the results were promising. In mice exhibiting Alzheimer’s-like brain changes, activating SST1 and SST4 boosted neprilysin levels and successfully reduced the buildup of amyloid beta. Crucially, this biochemical change resulted in improved memory and behavior without causing serious side effects.
“Our findings show that the brain’s own defence against amyloid beta can be strengthened by stimulating these receptors,” said Per Nilsson, docent at the Department of Neurobiology, Care Sciences and Society at Karolinska Institutet.
A Shift Toward Affordable Pill-Based Treatments
One of the most significant aspects of this discovery is its potential to democratize access to Alzheimer’s care. Current advanced treatments often involve complex antibody drugs that are expensive to manufacture and require intravenous administration. These existing therapies can also carry the risk of significant side effects, such as brain swelling or bleeding.
Because SST1 and SST4 are G protein-coupled receptors, they are considered ideal targets for traditional drug development. Medications that target this class of receptors can often be formulated as small molecules—pills—that are cheaper to produce and easier for patients to take.
“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 explained.
Related Advances: Nanotechnology Restores Brain Function
This new understanding of brain receptors builds on a wave of recent momentum in Alzheimer’s research focused on restoring the brain’s natural clearance mechanisms. Late last year, a separate international team co-led by University College London (UCL) and the Institute for Bioengineering of Catalonia (IBEC) demonstrated a different approach using nanotechnology.
In that study, researchers used “supramolecular” nanoparticles to repair the blood-brain barrier and restore vascular function in mice. Unlike the receptor-based approach, which targets enzyme production, this method focused on the brain’s vascular system. The nanoparticles acted as a drug themselves, triggering a cascade effect that cleared amyloid beta and other toxic molecules.
The results of the nanoparticle study were striking. Researchers observed a 50-60% reduction in amyloid beta levels in the brain just one hour after injection. Furthermore, the treatment reversed memory loss in older mice. In one experiment, 18-month-old mice treated with the nanoparticles exhibited behavior comparable to healthy, younger mice.
“The long-term effect comes from restoring the brain’s vasculature,” noted Giuseppe Battaglia, a lead author of the nanotechnology study. “We think it works like a cascade: when toxic species such as amyloid-beta accumulate, disease progresses. But once the vasculature is able to function again, it starts clearing amyloid-beta and other harmful molecules.”
The Future of Alzheimer’s Therapy
Both the recent receptor discovery and the nanotechnology breakthrough highlight a shifting paradigm in treating neurodegenerative diseases. Rather than simply attacking the plaques with external antibodies, scientists are finding ways to repair or reactivate the body’s intrinsic physiological processes.
Whether through stimulating specific receptors to boost enzyme activity or repairing the vascular “gatekeepers” of the brain, these approaches aim to restore balance to the brain’s environment. As research progresses, these “switches” and repair mechanisms could finally offer effective, accessible solutions for the millions of people living with Alzheimer’s disease.
