Poster abstracts

Poster number 84 submitted by Susan Xu

Investigating the mechanism underlying pyridazine-derivatives enhanced functional and structural plasticity of tripartite glutamatergic synapse

Susan Xu (NGP)

Abstract:
Tripartite synapse is formed by a pre-synapse, a post-synapse, and a peri-synaptic astrocytic process (PAP). Exosomes, a type of extracellular vesicles (EVs) carrying molecules such as microRNAs, proteins and lipids, can be released from the PAP to regulate synaptic activity. Changes in the function and structure of tripartite synapses have been found in Alzheimer’s disease (AD). We discovered that pyridazine-derivatives can enhance functional and structural plasticity of tripartite glutamatergic synapse. Efficacy studies of one of the pyridazine-derivatives in AD mouse models demonstrated therapeutic potential for clinical use. However, the underlying mechanism of the compound action has not been fully understood. In a previous study, we found that the compound action site is located at the PAP. A set of PAP proteins is rapidly upregulated following compound treatment, and a subset of these PAP proteins is locally synthesized. Recently, I found that a set of proteins immediately localizes to the plasma membrane of the PAP following compound treatment. These proteins include membrane trafficking proteins, endocytic proteins, adhesion proteins, cytoskeletal proteins, signaling proteins, receptors and transporters. Rab35, a small GTPase that regulates exosome secretion, was found to be increased on the plasma membrane. In light of these observations, I hypothesize that the compound activates a signaling pathway which results in localization of a set of proteins to the plasma membrane, and subsequently, a subset of these proteins is released from the PAP via exosomes to regulate synaptic activity. To test this hypothesis, I isolated EVs from mouse brains followed by size fractionation to obtain exosomes. Isolated exosomes were then assessed for concentration and size distribution by nanoparticle tracking analysis. Results showed increased secretion of exosome following compound treatment. Furthermore, exosomes were subjected to proteomic analysis. Results showed enrichment of RNA binding proteins, antioxidant proteins, signaling proteins, and enzymes in the exosomes following compound treatment. These results suggest that these proteins may release via exosome to regulate synaptic function.

Keywords: exosome, astrocytic process, synapse