A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation

International Journal of Biological Sciences 2026 Open access

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Authors: Ruomeng Li, Jing Yao, Wen Peng, Lizhen Zheng, Xueyin Wu, Xindong Shui, Xiaoqing Zheng, W N Tian, Long Wang, Ying Qiu Zhou, Xinglin Ruan, Pan Xiaodong
+4 more Tao Zhang, Yang Liu, Tae Ho Lee, Dongmei Chen
DOI: 10.7150/ijbs.131465
Cited by: 1

Abstract

, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.

Fields of Study & Subjects

Protein Degradation and Inhibitors Histone Deacetylase Inhibitors Research Chromatin Remodeling and Cancer

Publication details

Journal / source
International Journal of Biological Sciences
Publisher
Ivyspring International Publisher
Volume
22
Issue
9
Pages
4724–4746
Publication date
23 April 2026
Language
EN