A research team from the Neurosciences Institute (Ubneuro) of the University of Barcelona has discovered new molecular mechanisms related to cognitive decline associated with Alzheimer’s disease, the most common dementia. This study, conducted on animal models with the disease, describes the decisive role of the RTP801 protein in cells for the first time astrocyte During the progression of this neurodegenerative disease.
De Paper, published in Alzheimer and dementia – The most important publication of the Alzheimer’s Association – opens a new scenario for describing new therapeutic goals in the fight against the disease.
De studie werd uitgevoerd door onderzoeker Almudena Chicote en leden van het team onder leiding van professor Cristina Malagelada, van de faculteit Medicine and Health Sciences van de UB en Ubneuro, in samenwerking met experts van experts van het UB’s Productie- en Validatiecentrum van de Augusted Therapies (Create Piyer Biomedical Research Institute (IDIBOMEDISCHE EN BIOMEDISCHE Idegend Intitute Intitute (Idibedic and Biomedical Idegende Intitutes (Idibedic Intitutes (Idibomestitus) and the Biomedical Research Institute (Idibamestitus) and the Biomedical Research Institute. Diseases (Ciberned).
RTP801 -Protein, astrocytes and neurodegeneration
In Alzheimer’s disease, which still has no healing, there is an accumulation of β-amyloid plaques outside of neurons and of hyperphosphorylated tau protein buttons in neurons. The RTP801 -protein, encrypted by the DDIT4 Gene in hippocampal neurons, is involved in the process of neuro inflammation, neurotoxicity and disease progression, as detailed by the team in an earlier paper (Cell death and illness2021).
As with other diseases that change brain function and cause cell death, this pathology includes a complex interaction between different types of cells in the central nervous system. Now the new study describes for the first time the crucial role of the RTP801 protein in astrocytes, specific brain cells involved in neuro inflammation, synaptic regulation and homeostasis of the brain.
Astrocytes, previously considered passive supporting cells, act as active regulators of neurodegenerative processes, including the preservation of excitatory inhibiting balance and neuro-immune reactions. RTP801 is a stress response protein that is involved in neuronal dysfunction, but the specific role in astrocytes was not well known. “
Cristina Malagelada, UB’s Department of Biomedicin and Ciberned
With the help of gene therapy techniques, the team investigated the effects of silence RTP801 -Iwitexpression in dorsal hippocampal astrocytes in animal models of the disease. The study analyzed the impact of gene switch on spatial memory, parvalbumin-positive (PV+) internurons and functional brain connectivity, which are interconnected by the function of inhibiting neural circuits.
“In Alzheimer’s disease, the dysfunction of these circuits leads to cognitive disorders, emotional disruption and disruption of the activity of the brain network, which are important aspects of disease progression. Moreover, we have also investigated its influence on neuro -inflammatory markers, microgliosis, orar orerosis, orar orerosis -orsa -orthosis, or -out -orula -orar orerosis or -out -orula -orsa -orthosis, -called -Oerelliosis -Research -orsa. (Ubneuro and Inflammase -researcher Almudena Chicote (Ubneuro and Inflammas -Chicte (Ubneur and Inflammata Chicote (Ubneuro and Inflamm phase Almudena Chicote (Ubneuro and Inflammata and Inflammata Chicote (Ubneuro and and Inflammata and and Inflammata and and Inflammata and and Inflammata and and Inflammata and and Inflammata and and Inflammata and and Inflammata and and Inflammata and Inflammata and and Inflammata and Inflammata and and Inflammata en Inflammata and and Inflamm phase and Inflammata Chicote (Ubneur and Inflammata Chicote (Ubneur and Inflammata CHICE and Inflammata, explained. Ciberned), first author of the article.
According to the study, when RTP801 levels are reduced in astrocytes in the animal model of Alzheimer’s disease, the hyperconnectivity of these brain networks also decreases. That is why standardization of RTP801 would help to restore the connection connection of the brain network, similar to that of healthy individuals.
Metabolic and neural changes
The team also discovered that GABA levels – a neurotransmitter that is essential for braking the exciting of the brain – are reduced in animal models of Alzheimer’s disease. However, this condition can be partially reversed when RTP801 -Iwitexpression is silenced in astrocytes. These metabolic changes are linked to the loss of a specific type of GABA synthesizing PV+ internurons in the Hippocampus.
“That is why the RTP801 -protein can help with reversing part of the damage to PV+ internurons in the Hippocampus, and this can help to restore adequate GABA production and improve brain function,” notes Almudena Chicote.
The study also suggests that the different brain network connectivity – the hyperconnectivity or increased brain network activity – observed in some models can be explained by the toxicity of the RTP801 protein in PV+ neurons in the Hippocampus, which are important producers of GABA. “The reduction of RTP801 repaired these neurons partially and improved GABA levels,” says the researcher.
The team is planning to expand the lines of research to the in vitro Findings and validation The use of RTP801 -protein elimination in future therapeutic strategies to tackle Alzheimer’s disease.
Source:
Journal Reference:
Chicote – González, A .., et al .. (2025). Astrocytes, via RTP801, contribute to cognitive decline by disturbing Gabaergic -regulated connectivity and stimulating neuro inflammation in an Alzheimer’s mouse model from Alzheimer’s. Alzheimer and dementia. doi.org/10.1002/alz.70051.