RTP801 Astrocyte Protein Linked to Cognitive Decline in Alzheimer's Disease

A groundbreaking study by researchers at the University of Barcelona's Institute of Neurosciences (UBneuro) has unveiled new molecular mechanisms associated with cognitive decline in Alzheimer's disease, the leading cause of dementia. This investigation, conducted on animal models, highlights the significant role of the RTP801 protein in astrocytes during the progression of this neurodegenerative disorder.

Published in the journal Alzheimer's & Dementia, the findings pave the way for identifying potential therapeutic targets in combating the disease. The research team, led by Professor Cristina Malagelada and researcher Almudena Chicote, collaborated with experts from the university's Production and Validation Center of Advanced Therapies, the August Pi i Sunyer Biomedical Research Institute, and the Biomedical Research Networking Center on Neurodegenerative Diseases.

Alzheimer's disease is characterized by the accumulation of ?-amyloid plaques outside neurons and hyperphosphorylated tau protein aggregates within neurons. The RTP801 protein, encoded by the DDIT4 gene in hippocampal neurons, has been shown to play a role in neuroinflammation, neurotoxicity, and the progression of the disease, as detailed in previous studies.

This new research identifies the RTP801 protein's crucial function in astrocytes, specialized brain cells that are essential for neuroinflammation, synaptic regulation, and maintaining brain homeostasis. Previously thought to be merely supportive, astrocytes are now recognized as active participants in neurodegenerative processes, including managing the balance between excitatory and inhibitory signals and regulating neuroimmune responses.

Using gene therapy techniques, the research team silenced the expression of the RTP801 protein in dorsal hippocampal astrocytes in animal models of Alzheimer's disease. They assessed the effects of this gene silencing on spatial memory, parvalbumin-positive (PV+) interneurons, and functional connectivity within the brain. Dysfunction of these neural circuits is known to contribute to cognitive impairments, emotional dysregulation, and disruptions in brain activity, which are crucial aspects of Alzheimer's progression.

Results indicated that reducing RTP801 levels in astrocytes led to a decrease in the hyperconnectivity of brain networks typically seen in Alzheimer's models. Normalizing RTP801 expression could help restore brain connectivity to levels observed in healthy individuals.

The study also reported decreased levels of GABA, an essential neurotransmitter that inhibits brain excitability, in the Alzheimer's animal models. Notably, silencing RTP801 expression in astrocytes partially reversed this condition. Such metabolic alterations have been linked to the loss of specific GABA-producing PV+ interneurons in the hippocampus.

By silencing RTP801, researchers observed potential restoration of these PV+ interneurons in the hippocampus, which could enhance GABA production and improve overall brain function. Furthermore, the study suggests that the excessive brain network activity observed in some models may be attributed to the toxic effects of RTP801 on PV+ neurons, which are vital for GABA synthesis.

The research team intends to expand their investigation to further validate these findings and explore the therapeutic potential of RTP801 protein silencing in future Alzheimer's treatments.