2. Academic Validation
  3. Ferulic Acid Improves Synaptic Plasticity and Cognitive Impairments by Alleviating the PP2B/DARPP-32/PP1 Axis-Mediated STEP Increase and Aβ Burden in Alzheimer's Disease

Ferulic Acid Improves Synaptic Plasticity and Cognitive Impairments by Alleviating the PP2B/DARPP-32/PP1 Axis-Mediated STEP Increase and Aβ Burden in Alzheimer's Disease

  • Neurotherapeutics. 2023 Apr 20. doi: 10.1007/s13311-023-01356-6.
Yacoubou Abdoul Razak Mahaman 1 2 3,  Fang Huang 3,  Maibouge Tanko Mahamane Salissou 3 4,  Mohamed Bassirou Moukeila Yacouba 5,  Jian-Zhi Wang 1 3 6,  Rong Liu 3,  Bin Zhang 3,  Hong-Lian Li 3,  Feiqi Zhu 7,  Xiaochuan Wang 8 9 10 11
Affiliations

Affiliations

  • 1 Coinnovation Center of Neuroregeneration, Nantong University, Nantong, JS, 226001, China.
  • 2 Cognitive Impairment Ward of the Neurology Department, The Third Affiliated Hospital of Shenzhen University, 47 Youyi Rd., Shenzhen, Guangdong Province, 518001, China.
  • 3 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Huibei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4 College of Health, Natural and Agriculture Sciences, Africa University, Mutare, Zimbabwe.
  • 5 Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
  • 6 Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, 430056, China.
  • 7 Cognitive Impairment Ward of the Neurology Department, The Third Affiliated Hospital of Shenzhen University, 47 Youyi Rd., Shenzhen, Guangdong Province, 518001, China. zfqzsu2004@aliyun.com.
  • 8 Coinnovation Center of Neuroregeneration, Nantong University, Nantong, JS, 226001, China. wxch@mails.tjmu.edu.cn.
  • 9 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Huibei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wxch@mails.tjmu.edu.cn.
  • 10 Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, 430056, China. wxch@mails.tjmu.edu.cn.
  • 11 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China. wxch@mails.tjmu.edu.cn.
PMID: 37079191 DOI: 10.1007/s13311-023-01356-6
Abstract

The burden of Alzheimer's disease, the most prevalent neurodegenerative disease, is increasing exponentially due to the increase in the elderly population worldwide. Synaptic plasticity is the basis of learning and memory, but it is impaired in AD. Uncovering the disease's underlying molecular pathogenic mechanisms involving synaptic plasticity could lead to the identification of targets for better disease management. Using primary neurons treated with Aβ and APP/PS1 animal models, we evaluated the effect of the phenolic compound ferulic acid (FA) on synaptic dysregulations. Aβ led to synaptic plasticity and cognitive impairments by increasing STEP activity and decreasing the phosphorylation of the GluN2B subunit of NMDA receptors, as well as decreasing other synaptic proteins, including PSD-95 and synapsin1. Interestingly, FA attenuated the Aβ-upregulated intracellular calcium and thus resulted in a decrease in PP2B-induced activation of DARPP-32, inhibiting PP1. This cascade event maintained STEP in its inactive state, thereby preventing the loss of GluN2B phosphorylation. This was accompanied by an increase in PSD-95 and synapsin1, improved LTP, and a decreased Aβ load, together leading to improved behavioral and cognitive functions in APP/PS1 mice treated with FA. This study provides insight into the potential use of FA as a therapeutic strategy in AD.

Keywords

Alzheimer’s disease; Cognitive impairment; Ferulic acid; Increased intracellular calcium; PP2B/DARPP-32/PP1 axis; Synapses.

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