Modulating Amyloid Pathology–Neural Hyperexcitability Crosstalk for Alzheimer’s Disease Therapy

作者：Ying Wang, Jinfu Li, Ding Zhang, Yinyao Feng, Mengni Zhou, Chang Zhou, Dijia Wang, Gaolin Qiu, Wei Dai, Zhilai Yang, Yunjiao Zhang, Li Zhang, Xuesheng Liu, Jiqian Zhang · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.5c08317 · 被引用次数：5 · 研究领域：Functional Brain Connectivity Studies、Neural dynamics and brain function、Computational Drug Discovery Methods

Current therapies for Alzheimer’s disease (AD) primarily target amyloid-β (Aβ) pathology using monoclonal antibodies, yet their limited efficacy partly results from unintended exacerbation of neural hyperexcitability. This highlights a critical but under-appreciated link between Aβ clearance and neuronal network dysfunction. Here, we designed R@AClipo, a nanotherapeutic platform that codelivers the TREM2 agonist peptide COG1410 and the glutamate modulator riluzole via Angiopep-2–modified liposomes capable of crossing the blood–brain barrier. In AD model mice, R@AClipo upregulated TREM2 expression and enhanced microglial-mediated Aβ clearance. Concurrently, it reduced glutamate accumulation and mitigated neuronal hyperexcitability, as measured by in vivo fiber photometry. Notably, TREM2-driven Aβ clearance alone modestly reduced hyperexcitability, independent of riluzole, contrasting with the excitatory effects frequently associated with antibody-based Aβ therapies. This combinatorial strategy improved cognitive performance and restored neural activity patterns without observable toxicity. Together, these findings support a physiologically compatible strategy that targets the pathological crosstalk between Aβ accumulation and neural hyperexcitability, offering a promising avenue for AD intervention.