title: Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in α-Synucleinopathy.
abstract: OBJECTIVE
  Neuro-inflammation is common in α-Synucleinopathies and Tauopathies; and evidence suggests a link between the tyrosine kinase Abl and neurodegeneration. Abl upregulates α-Synuclein and promotes Tau hyper-phosphorylation (p-Tau), while Abl inhibitors facilitate autophagic clearance.
  
  
  METHODS
  A model of α-Synucleinopathy harboring human mutant A53T α-Synuclein and exhibits concomitant increase in murine p-Tau was used to determine the immunological response to Abl inhibition.
  
  
  RESULTS
  Age-dependent alterations of brain immunity, including loss of IL-10 and decreased levels of IL-2 and IL-3 were observed in old A53T mice. Brain CCL2 and CCL5 were decreased, but CX3CL1 remained constantly elevated. Young A53T mice exhibited differential systemic and central immune profiles in parallel with increased blood markers of adaptive immunity, suggesting an early systemic immune response. Tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib reduced brain and peripheral α-Synuclein and p-Tau and modulated blood immunological responses. TKIs did not affect brain IL-10, but they changed the levels of all measured blood immune markers, except CX3CL1. TKIs altered microglia morphology and reduced the number of astrocyte and dendritic cells, suggesting beneficial regulation of microglia.
  
  
  CONCLUSIONS
  These data indicate that tyrosine kinase inhibition affects neuro-inflammation via early changes of the peripheral immune profile, leading to modulation of the neuro-immune response to α-Synuclein and p-Tau.
authors: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C., 20007, USA.
authors: Michaeline L
authors: ML
authors: Hebron
authors: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C., 20007, USA.
authors: Irina
authors: I
authors: Lonskaya
authors: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C., 20007, USA.
authors: Paul
authors: P
authors: Olopade
authors: Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington D.C., 20007, USA.
authors: Sandra T
authors: ST
authors: Selby
authors: Neurorestoration Group, Movement Disorders Program, National Parkinson Foundation Center of Excellence, Georgetown University Hospital, Washington D.C., 20007, USA ; Deparment of Neurology, Georgetown University Hospital, Washington D.C., 20007, USA.
authors: Fernando
authors: F
authors: Pagan
authors: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C., 20007, USA ; Neurorestoration Group, Movement Disorders Program, National Parkinson Foundation Center of Excellence, Georgetown University Hospital, Washington D.C., 20007, USA.
authors: Charbel E-H
authors: CE
authors: Moussa
keywords: Abl; Bosutinib; Inflammation; Microglia; Nilotinib; Tau; α-Synuclein
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