Glial endozepines and synaptic deficits in neurodegeneration

• Applicant: Dr. Yuan Shi
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511905387

Within the central nervous system (CNS), dendritic spines act as postsynaptic components of neurons, rapidly changing morphology to reflect synaptic formation and disruption. These changes underpin cognitive processes in both healthy and pathological states, such as Alzheimer's disease (AD) and Lewy body dementia (LBD). During the initial phase of our DFG-funded project, we observed elevated levels of diazepam-binding inhibitor (DBI) secreted by cortical astrocytes in a mouse model of LBD. This DBI binds to the translocator protein (TSPO) in microglial mitochondria, leading to abnormal microglial engulfment of dendritic spines. While we confirmed that this DBI-TSPO dependent microglial phagocytosis of synaptic materials in LBD, cross-analysis of single-cell RNA sequencing datasets revealed that this signaling pathway is also enhanced in other neurodegenerative diseases, including AD. Thus, the DBI-TSPO pathway appears to be a fundamental mechanism of disease-induced synaptic damage. Though targeting the DBI-TSPO pathway offers a promising approach for mitigating synaptic pathology in neurodegeneration, its detection often occurs with significant spine loss, which is hard to reverse. Additionally, both DBI and TSPO have various physiological roles, making their direct inhibition potentially harmful. Therefore, we plan to explore opportunities to inhibit the pathological activation of this pathway at the earliest possible stage or to intercept its detrimental effects within microglia. Preliminary results from the second phase of our project suggest that hyperactive neurons, common in neurodegenerative diseases, may regulate astrocytic DBI production via lipoprotein-like particles (LLPs). Consequently, we plan to explore the underlying mechanisms and the pathological relevance of this event by manipulating neuronal activity both pharmacologically and chemogenetically (WP1). In parallel, we will examine the downstream effects of DBI-TSPO signaling in microglia. Our initial findings indicate a TSPO-dependent, mitochondria-mediated endo/lysosomal alteration in microglia, suggesting a mechanism for their increased phagocytic activity. We, therefore, plan to use super-resolution microscopy and organelle-specific proteomics to elucidate the TSPO/mitochondria-related functional and molecular changes of microglial endo/lysosomes. Collectively, the planned work, along with findings from the initial and second phases of our DFG-funded project, aims to uncover a tripartite (neuron-astrocyte-microglia) vicious loop that compromises synaptic integrity across neurodegenerative diseases. Moreover, this study will help identify optimal targets to interrupt this loop, potentially preserving cognitive function during neurodegeneration.

• DFG Programme: Research Grants