Astrocytes, Not Just Amyloid, Drive Alzheimer’s Memory Loss

Scientists have discovered that star-shaped brain cells called astrocytes fuel cognitive decline in Alzheimer’s disease through a stress-response protein that disrupts memory circuits and triggers inflammation.

The finding, published in Alzheimer’s & Dementia, reveals how cells once considered passive bystanders actively contribute to the neurodegenerative cascade.

Researchers at the University of Barcelona found that when they silenced the RTP801 protein specifically in astrocytes of mice with Alzheimer’s-like pathology, the animals regained spatial memory abilities and showed restored brain connectivity patterns. The work challenges traditional views of astrocytes as mere support cells, positioning them as key players in disease progression.

The Astrocyte Connection

“Astrocytes, previously considered passive support cells, act as active regulators of neurodegenerative processes, including the maintenance of excitatory-inhibitory balance and neuroimmune responses,” explained Cristina Malagelada from the university’s Department of Biomedicine, who led the research team.

The study focused on RTP801, a protein that increases under cellular stress conditions like heat shock or oxygen deprivation. While previous research had identified elevated RTP801 levels in Alzheimer’s patients’ hippocampal tissue—correlating with disease severity—this marks the first investigation into its specific role within astrocytes.

Using gene therapy techniques, the researchers injected viral vectors into the hippocampus of 5xFAD mice, an established Alzheimer’s model. These vectors carried genetic instructions to reduce RTP801 production exclusively in astrocytes, leaving other brain cells unaffected. After one month, they put the mice through behavioral tests, brain imaging, and biochemical analyses.

Memory Restoration and Brain Networks

The results were striking. Mice with reduced astrocytic RTP801 performed significantly better on spatial memory tasks, including the Morris water maze test where animals must locate a hidden platform. While control Alzheimer’s mice showed no learning improvement over six days of training, those with silenced RTP801 matched the performance of healthy animals.

Brain imaging revealed equally compelling changes. The Alzheimer’s mice normally exhibited hyperconnectivity—excessive communication between brain regions including the cingulate cortex, amygdala, and hypothalamus. This hyperactivity, while seeming beneficial, actually disrupts normal brain function. Silencing RTP801 normalized these connectivity patterns, restoring them to levels seen in healthy mice.

“The reduction of RTP801 partially restored these neurons and improved GABA levels,” noted first author Almudena Chicote. GABA, the brain’s primary inhibitory neurotransmitter, acts like biological brakes to prevent excessive neural activity. Alzheimer’s mice showed reduced GABA levels, but RTP801 silencing partially reversed this deficit.

Protecting Critical Brain Cells

The researchers discovered that RTP801 appears to damage parvalbumin-positive interneurons, specialized cells that produce GABA in the hippocampus. These interneurons are particularly vulnerable to oxidative stress and inflammation. In the Alzheimer’s model, both the number and size of these critical cells were reduced. However, mice with silenced astrocytic RTP801 showed partial recovery of these interneurons, especially in the dentate gyrus region.

This finding helps explain the memory improvements. Parvalbumin interneurons regulate the timing of neural circuits essential for memory formation. Their loss disrupts the delicate balance between excitation and inhibition in brain networks, contributing to cognitive dysfunction.

Inflammation and Future Directions

The study also documented how RTP801 promotes neuroinflammation through multiple pathways. Silencing the protein reduced markers of both astrogliosis (astrocyte activation) and microgliosis (immune cell activation) in the brain. It also decreased levels of inflammasome components—protein complexes that trigger inflammatory responses when activated inappropriately.

Key inflammatory proteins including NLRP1, NLRP3, and pro-caspase 1 all showed reduced levels when astrocytic RTP801 was suppressed. However, the researchers noted that these changes didn’t translate to measurable differences in most cytokine levels, suggesting the inflammatory response involves complex, multi-layered mechanisms.

The research team plans to expand their investigations to strengthen these findings and explore therapeutic applications. They acknowledge limitations in studying only male mice and intend to include female subjects in future work, given known sex differences in Alzheimer’s progression and inflammatory responses.

Therapeutic Implications

Could targeting RTP801 in astrocytes offer a new treatment avenue for Alzheimer’s disease? The Barcelona team believes so, though they emphasize the need for additional validation studies. Unlike approaches that target amyloid plaques—which have largely failed in clinical trials—focusing on astrocytic inflammation and circuit dysfunction addresses different aspects of disease pathology.

The researchers noted that RTP801 protein levels correlate with disease severity in human Alzheimer’s patients, making it an attractive therapeutic target. The protein is encoded by the DDIT4 gene, which responds to various cellular stresses including those present in neurodegenerative diseases.

What makes this approach particularly intriguing is its specificity. Rather than broadly suppressing brain activity or inflammation, targeting astrocytic RTP801 appears to selectively restore healthy neural circuit function while reducing harmful inflammatory processes. The treatment preserved spatial memory and anxiety-related behaviors without affecting amyloid plaque formation, suggesting it works through distinct mechanisms from current experimental therapies.

The findings add to growing evidence that glial cells—including astrocytes and microglia—play central roles in neurodegeneration. As researchers continue unraveling these complex cellular interactions, new therapeutic strategies may emerge that target the brain’s support network rather than just its neurons.