Alzheimer's disease is known for one devastating effect above all others. It steadily destroys brain cells and the connections between them, breaking down the neural networks that allow us to store and recall memories.
What remains far less certain is how this destruction begins. One leading explanation focuses on amyloid beta, a protein fragment that can accumulate in the brain and harm neurons. But scientists have also linked Alzheimer's to many other factors, including tau proteins, lysosomes, chronic inflammation, immune cells called microglia, and additional biological processes.
A Possible Link Between Two Major Theories
Researchers now believe they may have found a way to connect two of the most prominent ideas about how Alzheimer's develops. In a study published in Proceedings of the National Academy of Sciences, scientists report new evidence that amyloid beta and inflammation may act through the same molecular pathway. Both appear to converge on a specific receptor that signals neurons when to eliminate synapses, the contact points that allow brain cells to communicate.
The research was led by Wu Tsai Neurosciences Institute affiliate Carla Shatz, the Sapp Family Provostial Professor, along with first author Barbara Brott, a research scientist in Shatz's laboratory. The work received partial support from a Catalyst Award from the Knight Initiative for Brain Resilience, a program focused on reexamining the basic biology behind neurodegenerative diseases such as Alzheimer's.
The Role of a Synapse Pruning Receptor
One major component of the study builds on earlier work involving a receptor known as LilrB2. Shatz has studied this molecule for years. In 2006, she and her colleagues discovered that the mouse version of LilrB2 plays an essential role in synaptic pruning, a normal process during brain development and learning in adulthood.
Later findings connected this same receptor to Alzheimer's. In 2013, Shatz's team showed that amyloid beta can bind to LilrB2. When this happens, neurons are triggered to remove synapses. Importantly, experiments also showed that removing the receptor genetically protected mice from memory loss in an Alzheimer's disease model.
Inflammation and the Complement Cascade
The second major line of research examined an immune process known as the complement cascade. Under healthy conditions, this system releases molecules that help the body eliminate viruses, bacteria, and damaged cells.
However, inflammation is a well known risk factor for Alzheimer's disease. Recent studies have increasingly tied the complement cascade to excessive synaptic pruning and to neurological disorders. These findings led Shatz to question whether molecules involved in inflammation might interact with LilrB2 in the same way amyloid beta does.
Testing a New Hypothesis
To explore this possibility, the research team screened complement cascade molecules to see whether any could bind to the LilrB2 receptor. Only one molecule fit the bill. The protein fragment C4d attached strongly enough to raise the possibility that it could contribute directly to synapse loss.
The researchers then tested this idea in living animals. They injected C4d into the brains of healthy mice to observe the effects. "Lo and behold, it stripped synapses off neurons," Shatz said -- quite a surprise for a molecule researchers had previously thought had no function at all.
A Shared Pathway for Memory Loss
Taken together, the findings suggest that both amyloid beta and inflammation may drive synapse loss through the same biological mechanism. This raises the possibility that scientists may need to rethink how Alzheimer's disease causes memory to fade.
"There's an entire set of molecules and pathways that lead from inflammation to synapse loss that may not have received the attention they deserve," said Shatz, who is also a professor of biology in the School of Humanities and Sciences and of neurobiology in the School of Medicine.
Neurons as Active Participants
The results also challenge a widely held assumption in Alzheimer's research. Many scientists have believed that glial cells, the brain's immune cells, are primarily responsible for removing synapses in the disease. This study suggests neurons themselves play a more direct role.
"Neurons aren't innocent bystanders," Shatz said. "They are active participants."
Implications for Alzheimer's Treatment
This insight could have important implications for future therapies. Currently, the only FDA approved treatments for Alzheimer's aim to break apart amyloid plaques in the brain. According to Shatz, those drugs have produced limited benefits and significant risks.
"Busting up amyloid plaques hasn't worked that well, and there are a lot of side effects," such as headaches and brain bleeding, Shatz said. "And even if they worked well, you're only going to solve part of the problem."
A more effective approach may involve targeting receptors like LilrB2 that directly control synapse removal. By protecting synapses, Shatz said, it may be possible to preserve memory itself.
Study Authors and Funding
The study was authored by Barbara Brott, Aram Raissi, Monique Mendes, Caroline Baccus, Jolie Huang, and Carla Shatz from the Stanford University Department of Biology, Stanford Medicine's Department of Neurobiology, and Bio-X; Kristina Micheva from Stanford's Department of Molecular and Cellular Physiology; and Jost Vielmetter from the California Institute of Technology.
Funding support came from the National Institutes of Health (1R01AG065206 and 1R01EY02858), the Sapp Family Foundation, the Champalimaud Foundation, the Harold and Leila Y. Mathers Charitable Foundation, the Ruth K. Broad Biomedical Research Foundation, and the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neuroscience Institute Stanford University. Human Alzheimer's disease tissue samples were provided by the Neurodegenerative Disease Brain Bank at the University of California, San Francisco, which receives funding from the NIH (P01AG019724 and P50AG023501), the Consortium for Frontotemporal Dementia Research, and the Tau Consortium.
