Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial function in mouse models of Parkinson׳s disease.
The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results demonstrated that lesion of the LC could change microglial function in the brain, which led to enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors, and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by inflammation, however, was due to the inflammation in different brain regions rather than the depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting dopaminergic neuron degeneration by impacting the function of microglia in the midbrain.
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Ning
N
Yao
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China; Beijing Children׳s Hospital Affiliated to Capital Medical University, Beijing 100045, China.
Yanhong
Y
Wu
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Yan
Y
Zhou
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Lili
L
Ju
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Yujun
Y
Liu
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Rongkai
R
Ju
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Deyi
D
Duan
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China. Electronic address: xuqy@ccmu.edu.cn.
Qunyuan
Q
Xu
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D008125:Locus Coeruleus / Q000293:injuries / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000209:etiology*; D009638:Norepinephrine / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications* / Q000209:etiology / Q000473:pathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; C491049:Aif1 protein, mouse; D001596:Benzylamines; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; C012102:DSP 4; D009638:Norepinephrine
Inflammation; Locus coeruleus; Microglia; Parkinson׳s disease; Striatum; Substantia nigra