Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss
| Autor: | Mikko T Huuskonen, Xiaochun Xie, Pan Kong, Melanie D. Sweeney, Berislav V. Zlokovic, Kassandra Kisler, Erica J. Lawson, Zhonghua Dai, Nelly Chuqui Owens, Divna Lazic, Abhay P. Sagare, Zhen Zhao, Yaoming Wang, Axel Montagne, Angeliki M. Nikolakopoulou, Min Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Circulatory collapse Recombinant Fusion Proteins medicine.medical_treatment Neurotoxins Mice Transgenic Nerve Tissue Proteins Pleiotrophin Brain Ischemia Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Genes Reporter medicine Animals Promoter Regions Genetic Cells Cultured Neurons Mice Inbred C3H biology business.industry General Neuroscience Growth factor Neurodegeneration Endothelial Cells Shock medicine.disease Capillaries Mice Inbred C57BL Infusions Intraventricular 030104 developmental biology medicine.anatomical_structure Cerebrovascular Circulation Nerve Degeneration biology.protein Cancer research Cytokines Neuroglia Female Pericyte Carrier Proteins Pericytes business Neuroscience 030217 neurology & neurosurgery Neurotrophin |
| Zdroj: | Nature Neuroscience |
| ISSN: | 1546-1726 1097-6256 |
| DOI: | 10.1038/s41593-019-0434-z |
| Popis: | Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction. |
| Databáze: | OpenAIRE |
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