Abstract
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.
Highlights
Parkinson's disease (PD) is a common neurodegenerative disorder and the most common movement disorder
Activated microg‐ lia are commonly seen within the substantia nigra pars compacta (SNpc) of PD brains investigated at autopsy; these cells directly induce significant, highly detrimental neurotoxic effects by ex‐ cessive production of a large array of cytotoxic factors such as interleukin‐1β (IL‐1β), tumour necrosis factor‐α (TNF‐α), interleu‐ kin‐6 (IL‐6) and nitric oxide (NO).[13,14,15]
Since AQP4 was expressed in astrocytes but not in mi‐ croglia,[28,35,36,37] we further investigated the expression of transforming growth factor‐β1 (TGF‐β1) in astrocytes
Summary
Parkinson's disease (PD) is a common neurodegenerative disorder and the most common movement disorder. Mediators in neuroinflammatory responses.[11,12] Activated microg‐ lia are commonly seen within the substantia nigra pars compacta (SNpc) of PD brains investigated at autopsy; these cells directly induce significant, highly detrimental neurotoxic effects by ex‐ cessive production of a large array of cytotoxic factors such as interleukin‐1β (IL‐1β), tumour necrosis factor‐α (TNF‐α), interleu‐ kin‐6 (IL‐6) and nitric oxide (NO).[13,14,15] as an antigen‐ presenting cell (APC), activated microglia express costimulatory molecules, such as cluster of differentiation 40 (CD40), cluster of differentiation 80 (CD80; B7‐1) and cluster of differentiation 86 (CD86; B7‐2), that promote APC‐dependent T‐cell activation.[16,17,18] Subsequently, activated T cells injure neurons by cell contact‐de‐ pendent mechanisms that involve Fas ligand (FasL) and/or release of cytotoxic factors.[19] Attenuation of microglial activation can protect up to 90% of DNs in PD animal models.[20,21,22]. Our findings suggest a novel role for AQP4 in brain neurodegeneration and an opportunity for the development of new therapeutic approaches to treat neurodegenerative diseases
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