Research Paper Volume 14, Issue 19 pp 8077—8094

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Qian Guo1,2, *, , Gang Wu1,2, *, , Fang Huang1, , Zhen Wei1, , Jian-Zhi Wang1,2,3, , Bin Zhang1, , Rong Liu1, , Yang Yang4, , Xiaochuan Wang1,2,3,5, , Hong-Lian Li1, ,

  • 1 School of Basic Medicine, Key Laboratory of Education Ministry, Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  • 2 Co-innovation Center of Neuroregeneration, Nantong University, Nantong JS 226001, China
  • 3 Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
  • 4 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
  • 5 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen 518000, China
* Equal contribution

Received: July 15, 2022       Accepted: September 23, 2022       Published: October 12, 2022
How to Cite

Copyright: © 2022 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml in vitro, which is more than two times higher than Hup-A. Together, 2JY-OBZ4 showed promising therapeutic effects in AD cell models through regulating multiple targets. The research provides a new candidate for the therapeutic development of AD.


AD: Alzheimer’s disease; Aβ: Amyloid beta; AChE: Acetylcholinesterase; Hup-A: Huperzine A; NMDA: N-methyl-D-aspartate; BBB: Blood-brain barrier; GSK-3β: Glycogen synthase kinase-3β; PP2A: Protein phosphatase 2A; ELISA: Enzyme-linked immunosorbent assay; APP: Amyloid precursor protein; sAPPα: Secreted α segment; sAPPβ: Secreted β fragment; BACE1: β-secretase; PSEN1: Presenilin-1; MCI: Mild cognitive impairment; NFT: Neurofibrillary tangle; PTMs: Post-translational modifications; AChEI: Acetylcholinesterase inhibitor.