2. Academic Validation
  3. Modulating Amyloid Pathology-Neural Hyperexcitability Crosstalk for Alzheimer's Disease Therapy

Modulating Amyloid Pathology-Neural Hyperexcitability Crosstalk for Alzheimer's Disease Therapy

  • ACS Nano. 2025 Nov 4;19(43):37617-37632. doi: 10.1021/acsnano.5c08317.
Ying Wang 1,  Jinfu Li 1,  Ding Zhang 2,  Yinyao Feng 1,  Mengni Zhou 3,  Chang Zhou 2,  Dijia Wang 1,  Gaolin Qiu 1,  Wei Dai 1,  Zhilai Yang 1,  Yunjiao Zhang 4 5,  Li Zhang 6,  Xuesheng Liu 1,  Jiqian Zhang 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230022, P. R. China.
  • 2 Department of Anesthesiology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, P. R. China.
  • 3 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, P. R. China.
  • 4 School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.
  • 5 National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, P. R. China.
  • 6 Department of Urology, the First Affiliated Hospital of Anhui Medical University and Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Hefei 230022, P. R. China.
PMID: 41126442 DOI: 10.1021/acsnano.5c08317
Abstract

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.

Keywords

Alzheimer’s disease; amyloid-β; liposome; microglia; neural hyperexcitability.

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