Aquaporin-4 deficiency reduces TGF-β1 in mouse midbrains and exacerbates pathology in experimental Parkinson's disease

J Cell Mol Med. 2019 Apr;23(4):2568-2582. doi: 10.1111/jcmm.14147. Epub 2019 Jan 25.


Aquaporin-4 (AQP4), the main water-selective membrane transport protein in the brain, is localized to the astrocyte plasma membrane. Following the establishment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model, AQP4-deficient (AQP4-/- ) mice displayed significantly stronger microglial inflammatory responses and remarkably greater losses of tyrosine hydroxylase (TH+ )-positive neurons than did wild-type AQP4 (AQP4+/+ ) controls. Microglia are the most important immune cells that mediate immune inflammation in PD. However, recently, few studies have reported why AQP4 deficiency results in more severe hypermicrogliosis and neuronal damage after MPTP treatment. In this study, transforming growth factor-β1 (TGF-β1), a key suppressive cytokine in PD onset and development, failed to increase in the midbrain and peripheral blood of AQP4-/- mice after MPTP treatment. Furthermore, the lower level of TGF-β1 in AQP4-/- mice partially resulted from impairment of its generation by astrocytes; reduced TGF-β1 may partially contribute to the uncontrolled microglial inflammatory responses and subsequent severe loss of TH+ neurons in AQP4-/- mice after MPTP treatment. Our study provides not only a better understanding of both aetiological and pathogenical factors implicated in the neurodegenerative mechanism of PD but also a possible approach to developing new treatments for PD via intervention in AQP4-mediated immune regulation.

Keywords: Parkinson’s disease (PD); aquaporin-4 (AQP4); transforming growth factor-β1 (TGF-β1); α-synuclein (α-syn).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / administration & dosage
  • Animals
  • Aquaporin 4 / deficiency
  • Aquaporin 4 / genetics*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cell Line, Transformed
  • Dopamine / metabolism
  • Gene Expression Regulation
  • Inflammation
  • Male
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism*
  • Mesencephalon / pathology
  • Mice
  • Mice, Knockout
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neurotoxins / administration & dosage
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Primary Cell Culture
  • Probenecid / administration & dosage
  • Signal Transduction
  • Transforming Growth Factor beta1 / genetics*
  • Transforming Growth Factor beta1 / metabolism
  • Tyrosine 3-Monooxygenase / genetics*
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • Aqp4 protein, mouse
  • Aquaporin 4
  • Neurotoxins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • alpha-Synuclein
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Probenecid
  • Dopamine