Recently, a research team led by Professor Li Suxin from the School of Pharmacy at our university published a study titled “Nano-immunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment” in the prestigious journal PNAS. The first authors of the paper are Tian Limin and Long Guangyu, master's students from the School of Pharmacy at our university. Professor Li Suxin from the School of Pharmacy is the first corresponding author, and China Pharmaceutical University is the first corresponding institution.
The accumulation of Aβ plaques and inflammation in the brain are important pathological features of Alzheimer's disease (AD), but the molecular biological connection between the two remains unclear. Microglia are the primary immune cells in the brain, maintaining the homeostasis of Aβ uptake and clearance. Professor Li Suxin's team discovered that under pathological conditions, excess Aβ induces activation of the cGAS-STING pathway in microglia through a mechanistic damage mechanism, triggering a series of inflammatory responses. In turn, neuroinflammation further disrupts the balance of Aβ uptake and clearance, exacerbating Aβ deposition and forming a pathological vicious cycle.
Based on these findings, the team proposed an Aβ-STING synergistic immune suppression therapy (ASSIST). This is a nanomicelle formulation capable of crossing the blood-brain barrier, which competitively disaggregates Aβ plaques and prevents their reaggregation, thereby enabling Aβ to be selectively phagocytosed by microglia rather than neurons in an oligomeric form. Upon entering microglia, it releases STING inhibitors to block inflammatory signals, restore Aβ clearance function, reduce neuronal damage, and synergistically improve cognitive impairment.
This study elucidates the molecular feedback mechanism by which Aβ-induced mitochondrial damage leads to mtDNA leakage, which in turn drives cGAS/STING-mediated neuroinflammation and disrupts the Aβ uptake and clearance balance. Based on this mechanism, an innovative drug formulation was designed, providing new intervention targets and potential therapeutic strategies for AD. This work was supported by the National Key Research and Development Program, the National Natural Science Foundation of China, the Jiangsu Province Double Innovation Team, the National Key Laboratory of Multi-Target Natural Medicines, and the National Key Laboratory of Neurological and Oncological Drug Research.
Original article link: www.pnas.org/doi/10.1073/pnas.2427257122
Diagram
