Implications of astrocytic RTP801 in neuroinflammation and neurodegeneration in Alzheimer’s disease

Abstract

[eng] The central nervous system (CNS), consisting of the brain and spinal cord, is supported by various cells including neurons, glial cells, and blood vessel cells. Neurons are responsible for transmitting signals, while astrocytes, once considered merely support cells, are now recognized as vital for CNS function. Astrocytes maintain CNS balance, assist in brain defense, and regulate several processes. Historically, astrocytes were 7irst identi7ied in the mid-1800s and develop from radial glia, dividing and transforming into mature astrocytes during brain development. They continue to proliferate in the adult brain but at a low rate. Astrocytes are critical in maintaining CNS homeostasis, including regulating ions, water, and neurotransmitter levels. They also play a key role in energy supply to neurons by converting glucose into lactate. Moreover, astrocytes are essential for synaptic regulation, promoting synapse formation and stability, and maintaining the blood-brain barrier. Astrocytes also contribute to neurovascular coupling and waste clearance via the glymphatic system, and they are involved in regulating blood 7low and oxygen levels. In neuroin7lammatory and neurodegenerative diseases, astrocytes can become reactive, leading to dysfunction. In diseases like Alzheimer's and Parkinson's, astrocytes lose their ability to support neurons and remove toxic substances, contributing to disease progression. Astrocyte reactivity is in7luenced by various signaling pathways, but the mechanisms of their dysregulation remain unclear. Alzheimer’s disease is the most common form of dementia worldwide, affecting millions of people. It is both sporadic (1%) and hereditary, with age being the higher risk factor. Inherited Alzheimer’s disease is caused by mutations in the APP, PSEN1 or PSEN 2 genes. Having the APOE ε4 gene is the primary genetic risk factor for late-onset Alzheimer’s disease. The disease is characterized by cortical atrophy and enlargement of the ventricles. A central feature of AD is the accumulation of amyloid-β (Aβ)

peptides, derived from amyloid precursor protein, prone to forming plaques. These plaques are linked to cognitive decline, particularly in their oligomeric form. Another hallmark of AD is the formation of neuro7ibrillary tangles, caused by hyperphosphorylation of tau proteins, which disrupt neuron function and lead to cell death. Neuroin7lammation also plays a key role, with microglia and astrocytes contributing to both Aβ clearance and neurodegeneration through in7lammatory pathways like the NLRP3 in7lammasome, exacerbating synaptic loss and further progression of the disease. AD treatments are divided into symptomatic and disease-modifying categories, although no cure exists yet. Promising new diagnostic biomarkers and therapies focusing on prevention and early intervention represent the future direction of AD management. RTP801, is a stress-induced protein involved in regulating various cellular processes like metabolism, oxidative stress, autophagy, and cell fate. It plays a role in in7lammatory, metabolic, neurodegenerative diseases, and cancer. Its expression is upregulated by stressors like hypoxia, DNA damage, and metabolic imbalances. RTP801 is primarily located in the cytoplasm but also in mitochondria, cell membranes, and the nucleus. A key function of RTP801 is inhibiting the mTOR pathway, which regulates cellular growth and autophagy. Elevated levels of RTP801 are linked to neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's, where it suppresses mTOR activity, leading to neuronal damage. Its inhibition in disease models has shown potential therapeutic bene7its by preventing cognitive decline and reducing in7lammation. This thesis aims to explore astrocytic RTP801's contribution to neurodegeneration and neuroin7lammation in AD using the 5xFAD mouse model and a novel triculture in vitro model. The goals include determining its effects on cognitive de7icits, neuron morphology, functional connectivity, neuroin7lammatory pathways, and intercellular crosstalk, as well as assessing its role in Aβ clearance.