2. Academic Validation
  3. Wnt/β-catenin Pathway Activation Reverses Tau Hyperphosphorylation and β-Amyloid Accumulation Induced by Combined Manganese and Iron Exposure in PC12 Cells

Wnt/β-catenin Pathway Activation Reverses Tau Hyperphosphorylation and β-Amyloid Accumulation Induced by Combined Manganese and Iron Exposure in PC12 Cells

  • Biol Trace Elem Res. 2025 May 29. doi: 10.1007/s12011-025-04681-3.
Thanh-Tung Ho # 1 2,  Hai Huang # 1 2,  Yi-Ling Li # 1 2,  Zhi-Xin Huang 1 2,  Viet-Phuong-Nguyen Nguyen 3,  Galal A Al-Samhari 4,  Michael Aschner 5,  Zhao-Cong Li 6,  Yue-Ming Jiang 7 8
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Nanning, 530021, Guangxi, China.
  • 2 Key Laboratory of Prevention and Control of Highly Prevalent Diseases in Guangxi Colleges and Universities, Medical University of Guangxi, Nanning, 530021, China.
  • 3 Faculty of Traditional Medicine, Hue University of Medicine and Pharmacy, Hue University, Thua Thien Hue, 49000, Vietnam.
  • 4 Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 5 Department of Molecular Pharmacology at Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • 6 Institute of Brain and Mental Diseases, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, China. lizhaocong1064@163.com.
  • 7 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Nanning, 530021, Guangxi, China. ymjianggxmu@163.com.
  • 8 Key Laboratory of Prevention and Control of Highly Prevalent Diseases in Guangxi Colleges and Universities, Medical University of Guangxi, Nanning, 530021, China. ymjianggxmu@163.com.
  • # Contributed equally.
PMID: 40442456 DOI: 10.1007/s12011-025-04681-3
Abstract

Manganese and iron are essential trace elements involved in critical neuronal processes; however, excessive exposure to these metals is a significant risk factor for Alzheimer's disease (AD). While most previous studies have focused on single-metal neurotoxicity, the mechanisms underlying combined manganese and iron exposure remain unclear. In this study, we investigated the effects of manganese and iron exposure, both individually and in combination, on tau hyperphosphorylation, β-amyloid (Aβ) accumulation (particularly Aβ1-42), Apoptosis, and the involvement of the Wnt/β-catenin signaling pathway in PC12 cells. Our results demonstrated that both manganese and iron significantly increased GSK-3β expression and decreased β-catenin and c-Myc levels, indicating inhibition of the Wnt/β-catenin pathway. Although both metals enhanced tau hyperphosphorylation, APP amyloidogenic processing via increased BACE1 expression, and accumulation of Aβ1-42, manganese exposure predominantly exacerbated tau hyperphosphorylation, whereas iron preferentially promoted amyloidogenesis. Notably, combined exposure to manganese and iron did not further increase tau phosphorylation or Aβ1-42 accumulation beyond single-metal exposure levels, suggesting complex interactions rather than additive toxicity. Importantly, pharmacological activation of Wnt/β-catenin signaling using lithium chloride (LiCl) effectively reversed metal-induced tau phosphorylation, APP amyloidogenesis, Aβ1-42 accumulation, and neuronal Apoptosis. These findings provide novel insights into manganese- and iron-induced neurotoxicity and highlight the therapeutic potential of targeting Wnt/β-catenin signaling to mitigate metal-associated neurodegeneration in AD.

Keywords

AD; Iron; Manganese; Tau; Wnt/β-catenin; β-Amyloid.

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