Speaker
Description
Amyloid beta (Aβ) protein accumulation is a major hallmark of Alzheimer’s disease (AD), primarily occurring in the hippocampal region of the brain and associated with impaired microglial clearance mechanisms, oxidative stress, and chronic neuroinflammation. Growing evidence suggests that accumulated Aβ and oxidative stress affect bioenergetic pathways by inducing a metabolic shift in microglia from oxidative phosphorylation to aerobic glycolysis (Warburg effect), regulated by the mTOR-HIF-1α pathway and marked by significantly upregulated glycolytic enzymes such as Hexokinase 2 (HK2). HK2 is a rate-limiting enzyme that further promotes inflammasome activation and pro-inflammatory (M1) microglial polarization in the brain. However, inhibition of HK2 can reprogram the metabolism of microglia towards lipid metabolism/oxidation, favouring an anti-inflammatory M2 phenotype and enhancing Aβ clearance. In this study, we synthesised and characterised a lecithin-coated nanoparticle that encapsulates curcumin and 2-deoxy-D-glucose (2-DG) using the thin-film hydration method. The nanoparticle enables the selective HK2 inhibition, reduces excessive glycolysis and promotes Aβ clearance. Concurrently, curcumin mitigates oxidative stress and neuroinflammation; additionally, it also acts as a tracking agent due to its fluorescent properties. Collectively, this biocompatible nanotherapeutic strategy aims to provide a new avenue in nanomedicine for AD therapy by restoring microglial metabolic balance and neuroprotection with enhanced Aβ clearance.
