Intraventricular Creatine Treatment Attenuates Alzheimer's Disease-Related Neuropathological Changes and Memory Impairment via Inhibiting STAT1 Phosphorylation

  • ACS Chem Neurosci. 2025 Oct 1;16(19):3790-3800. doi: 10.1021/acschemneuro.5c00475.
Xiangqi Shao  1 ,  Jianru Sun  1 ,  Xue Wang  1  2 ,  Xiang-Sha Yin  1  2 ,  Zhen Chen  1  2 ,  Yuanyuan Xu  1 ,  Tao Wang  1 ,  Bo Yuan  1 ,  Wenying Qiu  1 ,  Fan Liu  1  2 ,  Yongmei Chen  1 ,  Chao Ma  1  2  3  4
Affiliations
  • 1. Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 10005, China.
  • 2. National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 10005, China.
  • 3. State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10005, China.
  • 4. Chinese Institute for Brain Research, Beijing 102206, China.
PMID: 40968664 DOI: 10.1021/acschemneuro.5c00475
Abstract

The importance of neuroinflammation in Alzheimer's disease (AD) has attracted increasing attention, and the functions of the STAT1 signaling pathway have also generated widespread interest. However, the role of STAT1 in AD-related neuroinflammation and memory impairment is unclear. Therefore, this study was undertaken to elucidate the roles of the STAT1 signaling pathway in the brain tissue of AD patients and mouse of an AD model. Our results revealed that STAT1 phosphorylation was largely colocalized with the neuronal marker NeuN. Compared with that in control (non-AD) brain tissues, STAT1 phosphorylation was significantly upregulated in the brain cortex and hippocampus of both AD patients and FAD mice. Intraventricular injection of creatine (STAT1 signaling inhibitor) significantly reduced the level of neuronal STAT1 phosphorylation in the brain cortex and markedly alleviated cognitive impairment in FAD mice. Furthermore, intraventricular creatine treatment also reduced the number of Aβ plaques and the level of IBA1 expression in IBA1-positive microglia in FAD mice. These findings indicate that STAT1 phosphorylation may play an important role in AD-related neuroinflammation and memory impairment. The alleviation effects of intraventricular creatine in FAD mice may suggest that STAT1 is a potential therapeutic target for the treatment of AD in humans.

Keywords
Alzheimer’s disease; STAT1; cognitive impairment; creatine; neuroinflammation; phosphorylation.
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