2. Academic Validation
  3. Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs

Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs

  • Cell. 2026 Apr 2;189(7):1923-1941.e26. doi: 10.1016/j.cell.2026.01.034.
Fei Teng 1,  Jing Liu 2,  Tongtong Cui 2,  Xiangtian Tan 3,  Kailun Liu 2,  Zongren Hou 2,  Li Zhou 3,  Yuanzhi Xie 3,  Rongqi Li 3,  Da Li 3,  Bojin Li 3,  Dongmei Wang 2,  Qi Zhou 4,  Baoyang Hu 5,  Wei Li 6
Affiliations

Affiliations

  • 1 Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 3 Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
  • 5 Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
  • 6 Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
PMID: 41785850 DOI: 10.1016/j.cell.2026.01.034
Abstract

Clearance of aberrant cerebral Amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effectively facilitate targeted degradation of extracellular proteins and enable transcytosis across the blood-brain barrier. In vivo administration of SPYTACs effectively reduces peripheral and cerebral Aβ burden, attenuates synapse loss, and improves cognitive function in 5×FAD mice at both prodromal and symptomatic stages. Notably, SPYTAC treatment shows fewer side effects, including intracerebral hemorrhage and inflammation, compared with conventional immunotherapies. The high modularity and genetic encodability enable SPYTACs to target customized disease-causing proteins, underscoring their therapeutic versatility and translational promise across diverse diseases driven by pathogenic proteins.

Keywords

AD; Alzheimer’s disease; Aβ; SPYTAC; amyloid-β; eTPD; extracellular targeted protein degradation.

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