Abstract
Background: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations.
Methods: We explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11-12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1β, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aβ40 and Aβ42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities.
Results: Intervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1β and TNFα but not IL-6. MW150 treatment also increased the IBA1+ microglia within a 15 μm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aβ40 and Aβ42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells.
Conclusions: Our results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.
Document Type
Article
Publication Date
4-5-2017
Digital Object Identifier (DOI)
https://doi.org/10.1186/s12974-017-0845-2
Funding Information
This research was supported in part by NIH R01 NS093920 (LVE) and U01 AG043415 (DMW).
Related Content
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Repository Citation
Zhou, Zhengqiu; Bachstetter, Adam D.; Späni, Claudia B.; Roy, Saktimayee M.; Watterson, D. Martin; and Van Eldik, Linda J., "Retention of Normal Glia Function by an Isoform-Selective Protein Kinase Inhibitor Drug Candidate That Modulates Cytokine Production and Cognitive Outcomes" (2017). Sanders-Brown Center on Aging Faculty Publications. 86.
https://uknowledge.uky.edu/sbcoa_facpub/86
Additional file 1: Table S1. Cytokines and Aβ MSD. Source data for cytokine data in Fig. 1 and Aβ data in Fig. 5.
12974_2017_845_MOESM2_ESM.xls (63 kB)
Additional file 2: Table S2. IHC assays. Source data for GFAP data in Fig. 2 and CD68 and CD45 data in Fig. 4.
12974_2017_845_MOESM3_ESM.xls (59 kB)
Additional file 3: Table S3. Confocal Imaris assays. Source data for microglia load in Fig. 2, plaque load in Fig. 5, and microglia/plaque data in Fig. 6.
12974_2017_845_MOESM4_ESM.xls (80 kB)
Additional file 4: Table S4. BV2 assays. Source data for Fig. 7.
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Notes/Citation Information
Published in Journal of Neuroinflammation, v. 14, 75, p. 1-12.
© The Author(s). 2017
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