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Laboratory of Brain Exosomes and Pathology - ExoBrain

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Laboratory of Brain Exosomes and Pathology - ExoBrain

In the new era of Precision Medicine, the diagnosis, prognosis and treatment of complex and multifactorial brain diseases such as Alzheimer's disease (AD) and depression are increasingly based on the evaluation of the individual’s lifestyle, risk factors and multilevel biological analyses that aim to clarify the degree of brain thology as well as the effectiveness of new therapeutic schemes in each, individual/patient.

The Laboratory of Brain Exosomes and Pathology – ExoBrain led by Dr Ioannis Sotiropoulos focuses on the understanding of different cellular mechanisms of AD (e.g. Aβ, Tau, neuroinflammation) and their relationship to brain exosomes; the later are small extracellular vesicles (EVs) secreted by cells and carry different biological material (e.g. proteins, RNA and DNA) from the cell of origin. Based on their multiple cargo, small EVs such as exosomes are suggested to transfer biological information about the health status of the cell/brain exhibiting a great biomarker potential (Figure 1). Emerging evidence suggest two roles of brain exosomes: a) brain exosomes are involved in the spreading of AD brain pathology between cells & brain regions and, b) brain exosomes collected at the peripheral blood may represent great biomarkers of brain pathology (Figure 1 - Gomes et al., Exper Neurol 2022). Our laboratory uses novel techniques for the collection, isolation and multiscale analysis of brain exosomes as well as brain-derived exosomes collected in the peripheral blood while we have developed a novel method for isolation of brain tissue exosomes from animals and humans (release method) (Gomes et al., Cell Com 2023).

Dr Sotiropoulos’ team research lines include:

  1. identify etiopathological mechanisms of stress in AD and depression;
  2. test novel therapeutic approaches (e.g. antisense oligonucleotides- ASOs);
  3. explore biomarker potential of exosomes.

Combining studies in cellular and animal AD models as well as humans, our research efforts focus on the clarification of the impact of chronic psychological stress on AD and depression, as emerging evidence support a causal relationship between the two disorders with stress being a potential connecting risk factor (Sotiropoulos et al., 2019; Dioli et al., 2023) (see Figure 2). Our studies have shown that chronic stress activates pathological mechanisms of AD (e.g. amyloid beta (Aβ) overproduction and accumulation of hypersphorylated Tau) leading to neuronal dysfunction/atrophy as well as memory and mood deficits (Monteiro-Fernandes et al., Mol Psych 2022; Sotiropoulos et al., J Neurosc 2011; Vaz-Silva et al., EMBO 2018). Importantly, these stress-driven detrimental effects are Tau-dependent as deletion of Tau attenuated various parameters of stress pathology (Lopes S et al. PNAS 2016; Cer Cortex 2016). We also described cellular mechanisms through which chronic stress leads to accumulation of pathological forms of Tau such as the dysfunction of protein degradation mechanisms (e.g. endolysosomal pathway and autophagy) leading to dysregulation of RNA-binding proteins and the formation of RNA granules (Stress granules; Vaz-Silva et al, EMBO 2018; Silva et al, Cell Death & Diff 2019) as well as exosome secretion (Gomes et al., Cell Comm 2023).

Another part of our work demonstrates novel Tau-dependent mechanisms underlying the stress-driven damage of brain plasticity in the adult brain. Focusing on neuronal synapses, we propose novel mechanisms of stress-induced synaptic dysfunction and atrophy through: a) pathological accumulation of Tau in the synapse that triggers dysregulation of glutamatergic receptor signaling and excitotoxicity (Lopes et al. PNAS 2016; Pinheiro et al, Mol Neurobio 2016) and, b) synaptic mitochondria dysregulation (Lopes et al. Cer Cortex 2016). Regarding neurogenesis, we showed that chronic stress reduces neurogenesis in both the hippocampus and the subventricular zone of the adult brain through the accumulation of hyperphosphorylated 4R-Tau isoform in neuroblasts & newborn neurons. Furthermore, in collaboration with different research institutions and pharma industry in Greece and abroad, the research work of our laboratory also includes the testing of the potent therapeutic or protective action of novel molecules against Stress pathology and AD, including antisense oligonucleotides (ASOs), microneurotrophins, cannabidiol and psychedelic substances (Figure 2).

The research area of the team supervised by Dr Zafiroula (Iro) Georgoussi focuses on the elucidation of the molecular mechanisms controlling the function of G protein-coupled receptors (GPCRs) using as model the opioid receptors (ORs). ORs are involved in pain perception, drug tolerance and dependence, while they also regulate responses affecting stress, inflammation and neurogenesis (Birgül Lyison et al., 2024).

Dr Georgoussi attempts to deduce:

ι) how different OR signaling directions are determined,

ii) which proteins apart the G protein ones modulate neuronal plasticity in the CNS iii) what signaling pathways are involved.

In this context, her team has determined that the different opioid receptor subtypes, μ, δ and κ, use the same signaling machinery for achieving distinct signaling pathways and physiological outcomes such as neuronal differentiation and neurite outgrowth by interacting with proteins whose function is altered upon opioid administration (Georgoussi et al., 2006, 2012; Georganta et al., 2010; 2013;  Fourla et al., 2012; Papakonstantinou et al., 2015; Pallaki et a., 2017, Karoussiotis et al., 2020).

At present, Dr Georgoussi’s team is investigating how alterations in OR signaling result in distinct cellular responses and how opioids are implicated in anxiety and stress-related behaviors. A new signaling pathway has been defined, which induces the autophagic machinery and consequent neuronal synaptic changes upon κ-opioid receptor (κ-ΟR) activation with selective agonists. In a related context, stress exposure was shown to promote κ-OR-dependent autophagy causing neuronal and synaptic changes in specific brain regions, which are reversed upon specific κ-OR antagonist administration with high clinical importance (Karoussiotis et al., 2022) (Figure 3).

Current objectives focus on the role of RGS4 protein in autophagy induction and synaptic modulation upon κ-OR activation, and on the differential signaling outcomes by different opioid ligands by defining the connection between autophagy and κ-OR signaling in anxiety and depression (Figure 3). Concurrently, the pharmacological characterization of bioactive compounds from the Greek flora, capable of modulating the activity of opioid and other GPCRs, is underway in the context of developing nutritional supplements that may alleviate pain or mood disorders

The research work led by Prof. Iatrou focuses on the manipulation of the olfactory functions of hematophagous insects with the goal of interfering with them and limit the transmission of infectious diseases to animal and human hosts. Insects have the potential to transmit a large variety of pathogens to humans and animals, causing a variety of vector-borne diseases (VBDs). Οne powerful, effective and safe control method is the use of long lasting and environmentally friendly repellents and anosmia-inducing agents that may interfere with insect olfaction and minimize the ability of mosquitoes and other blood-sucking insects to bite and transfer pathogens to their host organisms – see below, Figure 4.

Using the malaria mosquito vector Anopheles gambiae as model, Dr. Iatrou΄s ongoing studies focus on the discovery of volatile organic compounds (VOCs) of natural origin, which cause symptoms of anosmia in mosquitoes and other hematophagous insects. This is achieved through the functional inhibition of the common for all olfactory receptors and evolutionarily conserved olfactory co-receptor ORco, which is required for the functionality of essentially all olfactory receptors. Specifically, the studies focus on the discovery of natural micromolecules that bind to ORco and act as its antagonists and, consequently, as antagonists of practically all olfactory receptors (Figure 4). This is achieved through the use of a cellular platform for expressing ORco and measuring its activity ex vivo by a co-expressed reference photoprotein. Concurrently, the expression and isolation of recombinant ORco on a large scale is underway in order to determine its quaternary structure and enable the rational discovery of new volatile compounds that may cause its inhibition. Artificial intelligence methodologies for achieving the same goal based on the structural properties of bioactive VOCs are also in progress (representative references: Tsitoura & Iatrou, Front Cell Neurosci 2016; Thireou et al, Insect Biochem Mol Biol 2018; Kythreoti et al, J Biol Chem 2021).