UBneuro Researchers Uncover the Impact of Astrocytic RTP801 on Alzheimer’s Disease Progression

Researchers at UBneuro just published in “Alzheimer’s & Dementia”, the main journal of the american Alzheimer’s Association,a study that investigated the role of astrocytic RTP801 in cognitive decline in a mouse model of Alzheimer’s disease (5xFAD mice). The researchers used adeno-associated virus (AAV) vectors to silence RTP801 expression specifically in astrocytes of the dorsal hippocampus in WT and 5xFAD mice. They then conducted behavioral, MRI, and biochemical analyses to assess the effects of RTP801 silencing, specifically in astrocytes.

Around 2021, Malagelada’s lab published a study wich demonstrated that silencing RTP801 in hippocampal neurons of the 5xFAD Alzheimer’s disease (AD) model effectively prevented cognitive decline and neuroinflammation. Given the complex interplay between different brain cell types in AD pathogenesis, they sought to investigate whether this effect extended to astrocytes, a type of glial cell in the brain which play a crucial role in neuroinflammation, synaptic regulation, and overall brain homeostasis. In fact, silencing RTP801 in 5xFAD hippocampal neurons also downregulated the levels of RTP801 astrocytes, confirming this crosstalk between neurons and astrocytes.

Astrocytes, once considered passive support cells, are currently recognized as active regulators of neurodegenerative processes, including the maintenance of inhibitory-excitatory balance and neuroimmune responses. RTP801 is a stress-response protein implicated in neuronal dysfunction and has been found to contribute to AD-related pathology. However, its specific role in astrocytes remained unclear until now.

This novel study found that in the 5xFAD mouse model of AD, there are increased levels of RTP801 in the astrocytes and investigated its cell-specific functions. Building on previous findings, this study aimed to determine whether astrocytic RTP801 contributes to cognitive deficits, neuroinflammation, and aberrant brain network connectivity in AD.

What would happen to the Brain Function if we silenced RTP801 specifically in astrocytes in a context of Alzheimer disease?

To investigate the impact of silencing RTP801 on brain function, they used targeted gene therapy to decrease the levels of RTP801, specifically in astrocytes, and explored its impact on spatial memory, anxiety-like behavior, parvalbumin-positive (PV+) interneurons, and functional brain connectivity. All four factors are interconnected through the health and function of inhibitory neural circuits. Dysfunction of these circuits in AD leads to cognitive impairment, emotional dysregulation, and disrupted brain network activity, which are key aspects of disease progression. Additionally, they examined its influence on neuroinflammatory markers, including astrogliosis, microgliosis, and inflammasome activation.

When RTP801 levels in astrocytes are reduced, which would mean normalized as we find in phisiological state, the hyperconnectivity in these brain networks is also reduced. This leads to belive that normalizing RTP801 expression helps to bring the brain’s resting-state network connectivity closer to what is seen in healthy individuals.

Metabolic and Neuronal Changes in Response to RTP801 Silencing

In this study, researchers used Magnetic Resonance Spectroscopy (MRS) to measure various metabolites in three groups of mice: WT miCT (wild-type control), 5xFAD miCT (a mouse model of Alzheimer’s), and 5xFAD miRTP801 (the same Alzheimer’s model but with reduced RTP801 in astrocytes). Among their findings it is stated that GABA, an important inhibitory neurotransmitter, was reduced in the 5xFAD miCT group compared to the WT mice, but this reduction was partially reversed when RTP801 in astrocytes was silenced (miRTP801).

These metabolic changes were linked to the loss of GABAergic Parvalbumin+ (PV+) interneurons in the hippocampus, which produce GABA.Silencing astrocytic RTP801 restored the number of PV+ interneurons in the 5xFAD miRTP801 mice compared to the 5xFAD miCT mice.

“Overall, —as it states Dr. Almudena Chicote— this implies that by silencing RTP801, we can reverse some of the damage to PV+ interneurons in the hippocampus, which might help restore proper GABA production and improve brain function”. The current study suggests that the observed hyperconnectivity (increased brain network activity) in 5xFAD mice may be partly due to the toxicity of astrocytic RTP801 on hippocampal PV+ neurons, which are key producers of GABA. Reducing RTP801 partially restored these neurons and improved GABA levels.

Moreover, If astrocytic RTP801 promotes gliosis and inflammasome activation, targeting it could help reduce chronic inflammation and slow disease progression, making it a promising therapeutic target. These findings provide compelling evidence that astrocytic RTP801 plays a pivotal role in AD pathophysiology and may serve as a promising therapeutic target.

Even though further confirmation in female models is still needed to strengthen these findings, these in vitro results are indenibly promissing and must be studied further to validate RTP801 as a target to be silenced in AD.