title: Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.
abstract: Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4months in TgAPP and pre-plaque intracellular Aβ accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.
authors.affiliation: Department of Neurology, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C. 20007, USA.
authors.forename: I
authors.initials: I
authors.lastname: Lonskaya
authors.affiliation: Department of Neurology, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C. 20007, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Hebron
authors.affiliation: Department of Neurology, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C. 20007, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Selby
authors.affiliation: Department of Neurology, Memory Disorders Program, Georgetown University Medical Center, Washington D.C. 20007, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Turner
authors.affiliation: Department of Neurology, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington D.C. 20007, USA. Electronic address: cem46@georgetown.edu.
authors.forename: C E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D016207:Cytokines; D004791:Enzyme Inhibitors; D009570:Nitriles; D010446:Peptide Fragments; D011743:Pyrimidines; D011804:Quinolines; C075222:amyloid beta-protein (1-42); C471992:bosutinib; D011505:Protein-Tyrosine Kinases; C498826:nilotinib
keywords: CX3CL1; bosutinib; inflammation; nilotinib; plaque