title: Long-term polarization of microglia upon α-synuclein overexpression in nonhuman primates.
abstract: We have previously shown that persistent α-synuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) α-synuclein. However, A53T α-synuclein overexpression induced neurodegeneration that resulted in nigral dopaminergic cell death. Here, we analyze the microglia population in the midbrain of these animals by stereological quantification of Iba1+ cells. Our data here show that monkeys overexpressing A53T α-synuclein showed a long-term increase in microglia presenting macrophagic morphology. However, wt α-synuclein overexpression, despite the absence of dopaminergic cell death, resulted in a permanent robust increase of the microglia population characterized by a range of distinct morphological types that persisted after 1 year. These results confirm that the microglial response differs depending on the type of α-synuclein (wt/A53T) and/or whether α-synuclein expression results in cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, the microglial response is modulated by events related to α-synuclein expression in substantia nigra and persists in the long term. The data presented here is in agreement with that previously observed in a recombinant adeno-associated virus (rAAV) α-synuclein rat model, thereby validating both the findings and the model, and highlighting the translational potential of the rodent model to higher species closer to humans.
authors.affiliation: CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Barkholt
authors.forename: V
authors.initials: V
authors.lastname: Sanchez-Guajardo
authors.forename: D
authors.initials: D
authors.lastname: Kirik
authors.forename: M
authors.initials: M
authors.lastname: Romero-Ramos
mesh_terms: D000818:Animals; D002144:Callithrix; D002421:Caudate Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects*; D000229:Dependovirus / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D006684:HLA-DR Antigens / Q000096:biosynthesis; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D017628:Microglia / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects; D011699:Putamen / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D006684:HLA-DR Antigens; D051844:alpha-Synuclein