Published on: May 26, 2025
A new study published in Alzheimer’s & Dementia, the flagship journal of the Alzheimer’s Association, opens up promising new avenues for identifying therapeutic targets in the fight against Alzheimer’s disease.
The research was led by Almudena Chicote and the team of Professor Cristina Malagelada from the Faculty of Medicine and Health Sciences and UBneuro at the University of Barcelona (UB), in collaboration with experts from UB’s Production and Validation Center of Advanced Therapies (Creatio), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), and the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED).
Alzheimer’s disease, which currently has no cure, is marked by the buildup of β-amyloid plaques outside neurons and hyperphosphorylated tau tangles inside them. Previous work by the same team, published in Cell Death and Disease (2021), identified the RTP801 protein—encoded by the DDIT4 gene—as a contributor to neuroinflammation, neurotoxicity, and disease progression in hippocampal neurons.
This complex disease involves multiple interacting cell types in the brain. The new study is the first to uncover a critical role for RTP801 in astrocytes—glial cells that were once considered passive but are now known to actively regulate neurodegenerative processes, synaptic activity, and brain homeostasis. RTP801 is a stress-response protein implicated in neuronal dysfunction, but its role in astrocytes had not been previously explored in depth.
The research team used gene therapy to silence RTP801 expression specifically in dorsal hippocampal astrocytes in animal models of Alzheimer’s disease. They then evaluated the effects on spatial memory, PV+ (parvalbumin-positive) interneurons, and functional brain connectivity, all of which are interconnected through inhibitory neural circuits. According to Almudena Chicote, first author of the article, the dysfunction of these inhibitory circuits in Alzheimer’s contributes to cognitive decline, emotional instability, and abnormal brain network activity. The study also examined neuroinflammatory markers, including astrogliosis, microgliosis, and inflammasome activation.
Results showed that lowering RTP801 levels in astrocytes reduced abnormal hyperconnectivity in the brain, suggesting that normalizing its expression may help restore brain network activity to levels more typical of healthy individuals.
The team also discovered that levels of GABA, a neurotransmitter essential for reducing brain excitability, were diminished in Alzheimer’s models. This reduction was partially reversed when RTP801 was silenced in astrocytes. The GABA changes are linked to the loss of PV+ interneurons in the hippocampus. Silencing RTP801 appeared to help recover these neurons and improve GABA production, potentially enhancing brain function.
The findings further suggest that the hyperconnectivity observed in Alzheimer’s models may be caused in part by the toxic effects of RTP801 on PV+ neurons. By reducing RTP801, the researchers saw partial restoration of these neurons and better neurotransmitter balance.
The team now plans to expand their research with further in vitro studies and aims to validate RTP801 silencing as a potential therapeutic strategy for Alzheimer’s disease.
Source: https://web.ub.edu/en/web/actualitat/w/factors-alzheimer-progression
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