NILOTINIB AND BOSUTINIB MODULATE PRE-PLAQUE ALTERATIONS OF BLOOD IMMUNE MARKERS AND NEURO-INFLAMMATION IN ALZHEIMER%26apos;S DISEASE MODELS

作者：Lonskaya I; Hebron M L; Selby S T; Turner R S; Moussa C E H

来源：Neuroscience, 2015, 304: 316-327.

DOI：10.1016/j.neuroscience.2015.07.070

• plaque
• CX3CL1
• inflammation
• nilotinib
• bosutinib

Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuroinflammation 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 Ab plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex (R) ELISA. Plaque A beta was detected at 4 months in TgAPP and pre-plaque intracellular A beta accumulation (2.5 months) 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-alpha, IL-6, IL-1 alpha, IL-1 beta) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-gamma. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2 months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6 months 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.

• 出版日期2015-9-24