Silencing astrocytic RTP801 in 5xFAD mice adjustments purposeful connectivity. Credit score: Alzheimer’s & Dementia (2025). DOI: 10.1002/alz.70051
A analysis workforce on the College of Barcelona’s Institute of Neurosciences (UBneuro) has found new molecular mechanisms associated to the cognitive decline related to Alzheimer’s illness, the most typical dementia. This research, carried out on animal fashions with the illness, describes for the primary time the decisive position of the RTP801 protein in cells generally known as astrocytes through the development of this neurodegenerative illness.
The paper, revealed in Alzheimer’s & Dementia, opens a brand new situation for describing new therapeutic targets within the struggle towards the illness.
The research was carried out by researcher Almudena Chicote and members of the workforce led by Professor Cristina Malagelada, from the UB’s College of Drugs and Well being Sciences and UBneuro, in collaboration with specialists from the UB’s Manufacturing and Validation Middle of Superior Therapies (Creatio), the August Pi i Sunyer Biomedical Analysis Institute (IDIBAPS) and the Biomedical Analysis Networking Middle on Neurodegenerative Ailments (CIBERNED).
RTP801 protein, astrocytes and neurodegeneration
In Alzheimer’s illness, which nonetheless has no treatment, there may be an accumulation of β-amyloid plaques exterior neurons and of hyperphosphorylated tau protein buds inside neurons. The RTP801 protein, encoded by the DDIT4 gene in hippocampal neurons, is concerned within the means of neuroinflammation, neurotoxicity and illness development, as detailed by the workforce in a earlier paper.
As in different illnesses that alter mind operate and trigger cell demise, this pathology entails a fancy interplay between several types of cells within the central nervous system.
Now, the brand new research describes for the primary time the vital position of the RTP801 protein in astrocytes, particular mind cells concerned in neuroinflammation, synaptic regulation and mind homeostasis.
“Astrocytes, previously considered passive support cells, act as active regulators of neurodegenerative processes, including the maintenance of excitatory-inhibitory balance and neuroimmune responses. RTP801 is a stress response protein involved in neuronal dysfunction, but its specific role in astrocytes was not well known,” says Malagelada, from the UB’s Division of Biomedicine and CIBERNED.
Utilizing gene remedy methods, the workforce explored the results of silencing RTP801 protein expression in dorsal hippocampal astrocytes in animal fashions of the illness. The research analyzed the affect of gene silencing on spatial reminiscence, parvalbumin-positive (PV+) interneurons and purposeful mind connectivity, that are interconnected by means of the operate of inhibitory neural circuits.
“In Alzheimer’s disease, dysfunction of these circuits leads to cognitive impairment, emotional dysregulation and disruption of brain network activity, which are key aspects of disease progression. In addition, we also examined its influence on neuroinflammatory markers, specifically astrogliosis, microgliosis and inflammasome activation,” explains first creator of the article Chicote from UBneuro and CIBERNED.
Based on the research, when RTP801 ranges are decreased in astrocytes within the animal mannequin of Alzheimer’s illness, the hyperconnectivity of those mind networks additionally decreases. Due to this fact, normalization of RTP801 expression would assist to revive mind community connectivity much like that of wholesome people.
Metabolic and neural adjustments
The workforce additionally discovered that ranges of GABA—a neurotransmitter important for inhibiting mind excitability—are decreased in animal fashions of Alzheimer’s illness. Nevertheless, this situation may be partially reversed when RTP801 protein expression in astrocytes is silenced. These metabolic adjustments have been linked to the lack of a selected sort of GABA-synthesizing PV+ interneurons within the hippocampus.
“Therefore, silencing the RTP801 protein may help reverse some of the damage to PV+ interneurons in the hippocampus, and this could help restore adequate GABA production and improve brain function,” notes Chicote.
The research additionally means that the aberrant mind community connectivity—the hyperconnectivity or elevated mind community exercise—noticed in some fashions may very well be defined by the toxicity of the RTP801 protein in PV+ neurons within the hippocampus, that are key producers of GABA. “The reduction of RTP801 partially restored these neurons and improved GABA levels,” says the researcher.
The workforce plans to broaden the strains of analysis to strengthen the in vitro findings and validate the usage of RTP801 protein silencing in future therapeutic methods to deal with Alzheimer’s illness.
Extra info:
Almudena Chicote‐González et al, Astrocytes, through RTP801, contribute to cognitive decline by disrupting GABAergic‐regulated connectivity and driving neuroinflammation in an Alzheimer’s illness mouse mannequin, Alzheimer’s & Dementia (2025). DOI: 10.1002/alz.70051
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Astrocyte protein RTP801 could contribute to cognitive decline in Alzheimer’s illness (2025, Could 26)
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