P2.13. LIPID METABOLISM MODULATES MICROGLIAL PHAGOCYTOSIS OF AMYLOID-BETA
Izabela Lepiarz-Raba1, Taufik Hidayat2, Weronika Tomaszewska2, Ali Jawaid2, Sandra Binias3, Bartłomiej Gielniewski3, Jacek Miłek4, Magdalena Dziembowska4
1 Translational Research in Exposures and Neuropsychiatric Disorders (TREND), Nencki Institute of Experimental Biology PAS, Warsaw, Poland
2 Translational Neuropsychiatry Research Group, Łukasiewicz-PORT, Wrocław, Poland
3 Laboratory of Sequencing, Nencki Institute of Experimental Biology PAS, Warsaw, Poland
4 Department of Biology, University of Warsaw, Warsaw, Poland
INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, is characterized by abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ clearance is primarily the function of microglia, the brain-resident immune cells that are highly sensitive to environmental stimuli and respond to homeostatic changes via altering the release of inflammatory cytokines and phagocytosis. These functional adaptations in microglia are intricately linked to their metabolism, which provides a unique opportunity to harness microglial phagocytosis for selective Aβ clearance in AD without substantially harming healthy neurons.
AIM(S): To investigate how metabolic manipulation of microglia influences their capacity to phagocytose and degrade Aβ, with a focus on identifying mechanisms that enhance selective Aβ clearance without affecting healthy neuronal material.
METHOD(S): Aβ phagocytosis was tested in HMC3 human microglia following metabolic manipulation. Lipid starvation was induced by delipidation of the medium, and overall nutrient deprivation was achieved through serum starvation. Aβ uptake and degradation were quantified, and transcriptomic changes were assessed. Functional validation of candidate pathways was performed via knockdown of SREBF2.
RESULTS: Both lipid and serum starvation increased Aβ uptake in HMC3 microglia. However, efficient degradation of internalized Aβ was observed only under lipid starvation; serum starvation resulted in minimal degradation over 24 hours. Transcriptomic analyses revealed changes in pathways related to cholesterol biosynthesis, SREBF signaling, and steroid metabolism. Notably, knockdown of SREBF2 abolished the lipid starvation-induced enhancement of Aβ phagocytosis without impairing phagocytosis of healthy neurosynaptosomes.
CONCLUSIONS: These findings identify microglial SREBF signaling as a novel and selective target for enhancing Aβ clearance in AD. Targeting this pathway may allow for preferential removal of pathological Aβ while sparing healthy neurons. In vivo validation and clinical correlation using serum samples from AD patients are currently underway.
FINANCIAL SUPPORT: TREMENDOS:
EU Joint Programme–Neurodegenerative Disease Research (JPND) (TREMENDOS; UMO-2022/04/Y/NZ5/00122).