Astrocytes not only amyloid, but also drive memory loss in Alzheimer’s disease

Scientists have found that astrocytes, known as astrocytes in Alzheimer’s disease, have decreased cognition of fuel for fuel in fuel in Alzheimer’s disease.

This finding, published in Alzheimer’s and dementia, reveals how cells once thought passive bystanders actively contributed to the neurodegenerative cascade.

Researchers at the University of Barcelona found that when they silenced the RTP801 protein, the animals restored spatial memory and showed restored brain connectivity patterns when astrocytes were silenced specifically for Alzheimer’s disease mice. This work challenges the traditional view of astrocytes to merely support cells, positioning them as key players in disease progression.

Astrocyte junction

“Astrocytes (formerly considered passive support cells) act as active regulators of neurodegenerative processes, including maintaining excitatory inhibitory balance and neuroimmune response,” explains Cristina Malagelada, who leads the research team.

The study focused on RTP801, a protein that increases under cellular stress conditions, such as heat shock or oxygen deprivation. Although previous studies have identified elevated RTP801 levels in hippocampal tissue in Alzheimer’s patients (related to disease severity), this marks the first study of its specific role in astrocytes.

The researchers used gene therapy technology to inject viral vectors into the hippocampus of 5xfad mice, an established Alzheimer’s disease model. These vectors carry genetic indicators to reduce RTP801 production in astrocytes, leaving other brain cells unaffected. One month later, they performed behavioral testing, brain imaging and biochemical analysis in the mice.

Memory recovery and brain network

The results are surprising. Mice that lowered astrocytes RTP801 performed significantly better on spatial memory tasks, including the Morris water maze test, where animals had to find hidden platforms. Although control Alzheimer’s mice showed no learning progress over the six-day training, the silent RTP801 mice matched the performance of healthy animals.

Brain imaging reveals equally compelling changes. Mice with Alzheimer’s disease usually exhibit high connectivity – permeability between brain regions including the cingulate cortex, amygdala, and hypothalamus. Although this ADHD seems to be beneficial, it actually destroys normal brain function. Silent RTP801 normalizes these connectivity patterns, reverting them to levels seen in healthy mice.

First author Almudena Chicote notes, “The reduction in RTP801 partially restores these neurons and improves GABA levels.” The brain’s main inhibitory neurotransmitter, GABA, like a biological brake, prevents excessive neural activity. GABA levels were reduced in Alzheimer’s mice, but RTP801 silencing partially reversed this deficit.

Protect key brain cells

The researchers found that RTP801 appears to damage albumin-positive positive interneurons, specialized cells that produce GABA in the hippocampus. These interneurons are particularly susceptible to oxidative stress and inflammation. In Alzheimer’s model, the number and size of these critical cells are reduced. However, mice with silenced astrocyte RTP801 exhibit partial recovery of these interneurons, especially in the dentate gyrus region.

This finding helps explain memory improvements. Albumin interneurons regulate the time when neural circuits are essential for memory formation. Their losses disrupt the delicate balance between excitation and inhibition in the brain network, leading to cognitive dysfunction.

Inflammation and the direction of the future

The study also documented how RTP801 promotes neuroinflammation through multiple pathways. The protein of protein decreases the marker of astrocytes (astrocyte activation) and microglia (immune cell activation). It also lowers the levels of inflammasome components – protein complexes, which trigger an inflammatory response when improperly activated.

Key inflammatory proteins including NLRP1, NLRP3 and Pro-Caspase 1 all showed reduced levels when astrocyte RTP801 was inhibited. However, the researchers noted that these changes did not translate into measurable differences in most cytokine levels, suggesting that inflammatory responses involve complex multilayer mechanisms.

The research team plans to expand the investigation to strengthen these findings and explore therapeutic applications. They acknowledged the limitations of studying only male mice and intended to include female subjects in future work, given the known gender differences in Alzheimer’s disease progression and inflammatory response.

Therapeutic significance

Can RTP801 in astrocytes provide new treatments for Alzheimer’s disease? The Barcelona team believes that although they emphasize the need for other validation studies. Unlike methods targeting amyloid plaques, which have largely failed in clinical trials, focus on different aspects of astrocyte inflammation and circuit dysfunction involving disease pathology.

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

What makes this approach particularly interesting is its specificity. Targeting astrocyte RTP801 is not a widespread inhibition of brain activity or inflammation, and it seems to selectively restore healthy neural circuit function while reducing harmful inflammatory processes. This treatment preserves spatial memory and anxiety-related behaviors without affecting amyloid plaque formation, suggesting that it works through different mechanisms of current experimental therapies.

These findings add to the growing evidence that glial cells, including astrocytes and microglia, play a central role in neurodegeneration. As researchers continue to reveal these complex cell interactions, new therapeutic strategies for targeting the brain’s support networks rather than just its neurons may emerge.