P1.32. SORCS2 SHIELDS ASTROCYTES FROM AMYLOID BETA (AΒ) STRESS BY REGULATING P75 NTR SIGNALING
Ewelina Ziemlińska1, Vanessa Schmidt2, Thomas E. Wilnow2, Anna R. Malik1
1 University of Warsaw, Faculty of Biology, Warsaw, Poland
2 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
INTRODUCTION: Alzheimer’s disease (AD) is the leading cause of dementia, marked by amyloid-beta (Aβ) accumulation, inflammation, and neurodegeneration. Astrocyte dysfunction impacts lipid metabolism and proteostasis, contributing to AD progression. SorCS2 protects astrocytes under Aβ exposure, but its exact role remains unclear. The p75NTR contributes to apoptosis, with its activity being regulated by lipid homeostasis and S-palmitoylation, as well as influenced by membrane dynamics. A promising therapeutic molecule, LM11A-31, has been shown to downregulate p75NTR, leading to cognitive improvements in AD patients. However, the complex interplay between SorCS2, p75NTR, and lipid metabolism in astrocyte survival requires further investigation.
AIM(S): The study investigated SorCS2’s involvement in lipid homeostasis and p75NTR-mediated apoptosis in astrocytes exposed to Aβ.
METHOD(S): Primary astrocytes from wild-type (WT) and SorCS2-knockout (KO) mice were exposed to Aβ. Fluorescent lipid assays were performed to quantify cholesterol levels, microscopy-based analysis was conducted to examine lipid droplet formation, and Western blot and immunostaining were used to assess S-palmitoylation.
RESULTS: SorCS2 deficiency disrupts lipid metabolism and impairs lipid droplet accumulation in astrocytes. Elevated p75NTR protein levels were observed, accompanied by transcriptional upregulation. Preliminary data indicate that lipid abnormalities may induce aberrant S-palmitoylation, affecting the subcellular distribution of p75NTR, TRAF6, and p62 proteins involved in neurotrophin signaling and stress responses. Additionally, early observations suggest changes in plasma membrane lipid composition, potentially impacting membrane fluidity and trafficking dynamics.
CONCLUSIONS: This study clarifies SorCS2’s role in astrocyte survival, shedding light on lipid-driven astrocytic dysfunction and its implications for AD therapy
FINANCIAL SUPPORT: The Excellence Initiative – Research University for ARM, NCN „Opus” (2020/37/B/NZ3/00761) for ARM, NCN “Miniatura” (2024/08/X/NZ3/01728 ) for EZ.