id_885. CARGO-SPECIFIC REGULATION OF MICROGLIAL AΒ PHAGOCYTOSIS BY LIPID-RESPONSIVE TRANSCRIPTION FACTOR SREBF2
Izabela Lepiarz-Raba1, Taufik Hidayat2, Weronika Tomaszewska2, Ali Jawaid2, Sandra Binias3, Bartłmiej Gielniewski3, Jacek Miłek4, Magdalena Dziembowska4
1 Nencki Institute of Experimental Biology PAS, Translational Research in Exposures and Neuropsychiatric Disorders (TREND), 3 Pasteura Street, Warsaw, Poland
2 Łukasiewicz-PORT, Translational Neuropsychiatry Research Group, 147 Stablowicka Street, Wrocław, Poland
3 Nencki Institute of Experimental Biology PAS, Laboratory of Sequencing, 3 Pasteura Street, Warsaw, Poland
4 University of Warsaw, Department of Biology, 1 Miecznikowa Street, Warsaw, Poland
INTRODUCTION: Alzheimer’s disease (AD), the leading cause of dementia, is marked by abnormal accumulation of amyloid-β (Aβ) in the brain. Microglia, the brain’s resident immune cells, are responsible for Aβ clearance, and their phagocytic function is strongly influenced by metabolic and environmental states. Understanding how metabolic manipulation affects microglial Aβ handling may provide a route to selectively enhance pathological Aβ clearance while preserving healthy neuronal structures.
AIM(S): To investigate how metabolic perturbations, specifically lipid starvation and serum starvation modulate microglial Aβ uptake and degradation, and to identify molecular pathways regulating cargo-specific Aβ phagocytosis, with a focus on the role of SREBF2.
METHOD(S): Human HMC3 microglia were subjected to lipid starvation (medium delipidation) and serum starvation. Aβ uptake and degradation were analyzed under both conditions.In addition, transcriptomic profiling was performed using RNA sequencing to identify starvation-induced pathway changes. Lastly, functional validation included siRNA-mediated knockdown of SREBF2 to assess its role in lipid-starvation–enhanced Aβ phagocytosis and cargo specificity.
RESULTS: Both lipid and serum starvation induced major transcriptomic changes, particularly in cholesterol biosynthesis, SREBF signaling, and steroid metabolism pathways, and although Aβ uptake increased under both conditions, efficient degradation occurred only during lipid starvation, whereas serum starvation impaired degradation and led to intracellular Aβ accumulation; furthermore, knockdown of SREBF2 abolished the lipid starvation–induced enhancement of Aβ phagocytosis without affecting neurosynaptosome uptake, demonstrating cargo-specific regulation.
CONCLUSIONS: SREBF2-dependent cholesterol metabolic signaling is a key regulator of Aβ uptake and degradation. This pathway represents a promising and selective therapeutic target for enhancing microglial Aβ clearance in AD.
FINANCIAL SUPPORT: EU Joint Programme – Neurodegenerative Disease Research (JPND) [TREMENDOS; UMO-2022/04/Y/NZ5/00122]