Study uncovers new molecular mechanisms linked to Alzheimer's cognitive decline

A research team at the University of Barcelona's Institute of Neurosciences (UBneuro) has discovered new molecular mechanisms related to the cognitive decline associated with Alzheimer's disease, the most common dementia. This study, carried out on animal models with the disease, describes for the first time the decisive role of the RTP801 protein in cells known as astrocytes during the progression of this neurodegenerative disease.

The paper, published in Alzheimer's & Dementia — the main publication of the Alzheimer's Association —, opens a new scenario for describing new therapeutic targets in the fight against the disease.

The study was carried out by researcher Almudena Chicote and members of the team led by Professor Cristina Malagelada, from the UB's Faculty of Medicine and Health Sciences and UBneuro, in collaboration with experts from the 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).

RTP801 protein, astrocytes and neurodegeneration

In Alzheimer's disease, which still has no cure, there is an accumulation of β-amyloid plaques outside neurons and of hyperphosphorylated tau protein buds inside neurons. The RTP801 protein, encoded by the DDIT4 gene in hippocampal neurons, is involved in the process of neuroinflammation, neurotoxicity and disease progression, as detailed by the team in a previous paper (Cell Death and Disease, 2021).

As in other diseases that alter brain function and cause cell death, this pathology involves a complex interaction between different types of cells in the central nervous system. Now, the new study describes for the first time the critical role of the RTP801 protein in astrocytes, specific brain cells involved in neuroinflammation, synaptic regulation and brain 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."

Cristina Malagelada, UB's Department of Biomedicine and CIBERNED

Using gene therapy techniques, the team explored the effects of silencing RTP801 protein expression in dorsal hippocampal astrocytes in animal models of the disease. The study analysed the impact of gene silencing on spatial memory, parvalbumin-positive (PV+) interneurons and functional brain connectivity, which are interconnected through the function 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 researcher Almudena Chicote (UBneuro and 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. Therefore, normalization of RTP801 expression would help to restore brain network connectivity similar to that of healthy individuals.

Metabolic and neural changes

The team also found that levels of GABA — a neurotransmitter essential for inhibiting brain excitability — are reduced in animal models of Alzheimer's disease. However, this condition can be partially reversed when RTP801 protein expression in astrocytes is silenced. These metabolic changes have been linked to the loss of a specific type of GABA-synthesising PV+ interneurons in 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 Almudena Chicote.

The study also suggests that the aberrant brain network connectivity — the hyperconnectivity or increased brain network activity — observed in some models could be explained by the toxicity of the RTP801 protein in PV+ neurons in the hippocampus, which are key producers of GABA. "The reduction of RTP801 partially restored these neurons and improved GABA levels", says the researcher.

The team plans to expand the lines of research to strengthen the in vitro findings and validate the use of RTP801 protein silencing in future therapeutic strategies to address Alzheimer's disease.