P1.40. BRAIN ENERGY IMBALANCE AND INFLAMMATORY RESPONSE IN BBB DYSFUNCTION IN APOE-/-/LDLR-/- MICE DURING HYPERCHOLESTEROLEMIA
Ewelina Czuba-Pakuła1, Iwona Pelikant-Małecka2, Sebastian Głowiński3, Grażyna Lietzau1, Ryszard T. Smoleński4, Przemysław Kowiański1,3
1 Medical University of Gdańsk, Department of Anatomy and Neurobiology, 1 Dębinki Str., 80-211 Gdańsk, Poland
2 Medical University of Gdańsk, Division of Medical Laboratory Diagnostics ‑ Fahrenheit Biobank BBMRI.pl, 1 Dębinki Str., 80-211 Gdańsk, Poland
3 Pomeranian University of Słupsk, Department of Health Sciences, 64 Bohaterów Westerplatte Str., 76-200 Słupsk, Poland
4 Medical University of Gdańsk, Department of Biochemistry, 1 Dębinki Str., 80-211 Gdańsk, Poland
INTRODUCTION: Hypercholesterolemia is a key metabolic disturbance frequently associated with an increased risk of cardiovascular and neurodegenerative disorders. Growing evidence suggests that elevated cholesterol levels adversely affect the neurovascular unit (NVU), leading to blood-brain barrier (BBB) dysfunction, altered cerebral energy metabolism, and enhanced neuroinflammatory processes.
AIM(S): This study aimed to investigate how chronic hypercholesterolemia alters BBB integrity and inflammatory signaling in the brain, with a specific focus on extracellular adenine nucleotide metabolism in brain microvascular endothelial cells using a genetically modified mouse model.
METHOD(S): Three-month-old ApoE-/-/LDLR-/- double knockout mice and age-matched C57BL/6 control mice were used. The expression and activity of e-NTPDase, ecto-5'-NT, and eADA were assessed by HPLC. BBB integrity was examined using immunofluorescent detection of isothiocyanate-dextran (FD40). Levels of pro-inflammatory cytokines IL-1β and IL-6 were measured with ELISA.
RESULTS: In hypercholesterolemic mice, we observed a significant increase in eADA activity, elevated BBB permeability indicated by greater FD40 leakage, and increased concentrations of IL-1β and IL-6 in brain tissue compared to controls.
CONCLUSIONS: Hypercholesterolemia leads to impaired brain energy metabolism, BBB disruption, and a pro-inflammatory microenvironment. The observed metabolic shift toward inosine synthesis may reflect a neuroprotective and immunomodulatory response aimed at preserving endothelial cell viability.
FINANCIAL SUPPORT: This study was supported by statutory funding from the Medical University of Gdańsk.