Elucidating the protective role of astrocytic SORCS2 function in neurodegenerative disease.

• Applicant: Meagan Kitt, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525143290

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder characterized by accumulation of amyloid-ß peptides which aggregate into neurotoxic oligomers and senile plaques, causing synaptic dysfunction and cognitive decline in millions of patients worldwide. There are no existing treatments to slow or reverse disease progression. Recent findings now have identified glial cells as important players in AD pathology, focusing our attention on new disease mechanisms but also on novel targets for therapeutic intervention. With relevance to my proposal, evidence suggests that astrocytes are of importance in AD as they are crucial for the brain response to stress, as imposed by amyloid burden. In line with this hypothesis, latest work by the host lab has identified an intracellular sorting receptor SORCS2 that is upregulated in astrocytes in response to brain injury and that causes a massive increase in amyloid burden when inactivated in mouse models. Here, I will elucidate the molecular mechanisms of SORCS2 action important for astrocyte responses in AD. Initially, I will characterize the consequences of SORCS2 deficiency in a transgenic mouse model of AD by assessing hallmark signs of pathology, including plaque load, gliosis, and cell death. Next, I will zoom-in on the cell-type specific consequences of SORCS2 deficiency by functionally characterizing pure populations of astrocytes, microglia, and neurons, sorted from SORCS2-deficient mouse brains. Finally, I will validate the cell type-specific actions of SORCS2 in iPSC-derived human brain cell types to validate the relevance of this receptor for human disease and to identify its molecular mode of action, using global proteomics and functional assays. Ultimately, my studies will contribute to a better understanding of the role of astrocytes in human AD and corroborate SORCS2 as novel player, but also therapeutic target in combating this devastating disorder.

• DFG Programme: WBP Position