Targeting Peripheral and Central Pathways to Combat Neuroinflammation and Delirium after Brain Injury

Serum Amyloid A-1 (SAA-1), a crucial acute-phase protein, is significantly upregulated during inflammation, associating with high-density lipoprotein (HDL) and modulating immune responses and tissue repair. Elevated SAA-1, however, is implicated in chronic inflammatory diseases and neurodegenerative conditions. This project investigates the role of SAA-1 in neuroinflammation and cognitive deficits following traumatic brain injury (TBI), particularly in Alzheimer’s-like pathology. We will use targeted siRNA within liposomes to selectively inhibit hepatic SAA-1 production, isolating peripheral SAA-1 effects on neuroinflammatory markers and behavior in TBI models. Parallel experiments will use adeno-associated viral vectors to knock down brain-derived SAA-1, assessing neuroinflammation and behavior to differentiate peripheral versus central SAA-1 contributions. Additionally, we will combine both liver and brain-specific knockdowns to evaluate potential synergistic effects in mitigating neuroinflammatory damage. Complementary studies will track exogenous, radiolabelled SAA-1-HDL complexes crossing the blood-brain barrier to elucidate SAA-1’s brain entry mechanisms and impact on neuroinflammation. This project aims to clarify SAA-1’s contributions to delirium post-TBI, potentially guiding targeted interventions to mitigate neurocognitive symptoms.