Taulipro rescues mitochondrial dysfunction and inhibits cGAS–STING neuroinflammation in Aβ-driven Alzheimer's disease models

<title>Abstract</title> <p>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which effective multitarget therapies remain unavailable. Mitochondrial dysfunction and consequent cytoplasmic leakage of mitochondrial DNA (mtDNA) activate the cGAS-STING neuroinflammatory cascade, constituting a critical upstream pathogenic event in AD; however, no therapeutic agent specifically targeting this mtDNA leakage step has been developed. Here we report Taulipro, a co-crystal compound comprising taurine, lithium, and L-proline (molar ratio 1.5:1:1), characterized by ¹H NMR, PXRD, ICP-MS, and DSC. Using Aβ42 oligomer-challenged SH-SY5Y cells and 5×FAD mice (16-week oral gavage), we assessed mitochondrial function, cytoplasmic mtDNA leakage, cGAS–STING pathway activation, Aβ pathology, and neuroinflammatory markers. Taulipro reversed Aβ42-induced mitochondrial dysfunction including ROS accumulation, membrane potential depolarization, mPTP opening, ATP depletion, and Ca²⁺ overload and substantially reduced cytoplasmic mtDNA levels, outperforming equimolar taurine, LiCl, and physical mixture. In 5×FAD mice, Taulipro reduced Aβ plaque burden across the DG, CA3, cortex, and thalamus, suppressed cGAS-STING-TBK1-IRF3 signaling, and attenuated downstream p-NFκB, TNFα, and IL-18, with superior efficacy compared with Li₂CO₃ or taurine monotherapy. These results establish a mechanistic link between mitochondrial mtDNA leakage and cGAS-STING-driven neuroinflammation in AD, and identify Taulipro as a promising multitarget candidate for AD therapy.</p>