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

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 <i>in vivo</i> 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.