Alzheimer’s disease may deceive the brain into erasing its own memories by activating a molecular switch that prompts neurons to eliminate their connections. Research led by the Wu Tsai Neurosciences Institute at Stanford University has uncovered that both amyloid beta and inflammatory signals converge on the same receptor, leading to synapse loss. This finding suggests a potential new avenue for treatment, focusing on the receptor rather than solely targeting amyloid beta.
The study, published on January 26, 2026, in the journal Proceedings of the National Academy of Sciences, connects two significant theories regarding Alzheimer’s progression. While amyloid beta has long been implicated in neuronal damage, researchers are increasingly recognizing the role of inflammation and other biological processes. The research team, led by Carla Shatz, the Sapp Family Provostial Professor, and first author Barbara Brott, emphasizes the need to explore these interconnected pathways.
Investigating Synapse Pruning Mechanisms
A central element of this research involves a receptor known as LilrB2, which has been studied by Shatz for over a decade. Previous findings indicated that this receptor is vital for synaptic pruning, a natural process in brain development and learning. In 2013, her team discovered that amyloid beta can bind to LilrB2, triggering neurons to remove synapses. Notably, genetic modifications that removed this receptor in mice provided protection against memory loss in models of Alzheimer’s disease.
In parallel, the study examined the complement cascade, an immune response mechanism that helps the body eliminate pathogens and damaged cells. While essential for healthy functioning, inflammation—often a precursor to Alzheimer’s—has been linked to excessive synaptic pruning. Shatz and her team set out to determine if inflammatory molecules could interact with LilrB2 similarly to amyloid beta.
New Findings on Neuronal Activity
The researchers screened various molecules within the complement cascade and identified C4d, a protein fragment that binds effectively to LilrB2. Experiments demonstrated that injecting C4d into healthy mice resulted in the loss of synapses, signaling a significant role for this previously overlooked molecule.
This research challenges the long-held belief that glial cells, which serve as the brain’s immune defense, are primarily responsible for synaptic loss in Alzheimer’s. Shatz remarked, “Neurons aren’t innocent bystanders. They are active participants.” This insight could reshape how scientists approach Alzheimer’s treatment strategies, moving beyond the current focus on amyloid plaques.
Therapies targeting LilrB2 could offer a more effective solution for preserving memory. Existing FDA-approved treatments primarily aim to dismantle amyloid plaques but have shown limited success and notable side effects, including headaches and brain bleeding. Shatz noted, “Busting up amyloid plaques hasn’t worked that well, and there are a lot of side effects. Even if they worked well, you’re only going to solve part of the problem.”
The implications of this study extend beyond academic interest; they represent a potential shift in therapeutic strategies that could significantly impact patients suffering from Alzheimer’s disease. By focusing on the receptors that control synapse removal, researchers may develop treatments that better protect memory functions.
The study’s authors include Barbara Brott, Aram Raissi, Monique Mendes, Caroline Baccus, Jolie Huang, and Carla Shatz from Stanford University, along with Kristina Micheva from Stanford’s Department of Molecular and Cellular Physiology, and Jost Vielmetter from the California Institute of Technology. Financial support for this research came from the National Institutes of Health and several foundations dedicated to advancing understanding of neurodegenerative diseases.
In summary, this groundbreaking research not only sheds light on the mechanisms behind memory loss in Alzheimer’s but also opens new avenues for treatment that could alter the landscape of how this devastating disease is managed.
