Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis

Ciara Pedicone, Sandra Fernandes, Otto M. Dungan, Shawn M. Dormann, Dennis R. Viernes, Arijit A. Adhikari, Lydia B. Choi, Ebbing P. De Jong, John D. Chisholm, William G. Kerr

Research output: Contribution to journalArticle

Abstract

We show here that both SHIP1 (Inpp5d) and its paralog SHIP2 (Inppl1) are expressed at protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function, we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact on microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size, and phagocytosis of dead neurons and amyloid beta (Aβ)1-42 by microglia in vitro We show that one of the more-potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier. Consistent with this, K161 increases the capacity of CNS-resident microglia to phagocytose Aβ and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible, and suggest that dual inhibition of the SHIP1 and 2 paralogs can provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's disease and, possibly, other types of dementia where increased microglial function could be beneficial.

Original languageEnglish (US)
JournalJournal of cell science
Volume133
Issue number5
DOIs
StatePublished - Jan 10 2020

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Microglia
Homeostasis
Phagocytosis
Neurons
Aptitude
Blood-Brain Barrier
Dementia
Alzheimer Disease
Water
Proteins

Keywords

  • Alzheimer's disease
  • beta-amyloid
  • Microglia
  • Phagocytosis
  • SH2-containing inositol phosphatases
  • SHIPi

ASJC Scopus subject areas

  • Cell Biology

Cite this

Pedicone, C., Fernandes, S., Dungan, O. M., Dormann, S. M., Viernes, D. R., Adhikari, A. A., ... Kerr, W. G. (2020). Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. Journal of cell science, 133(5). https://doi.org/10.1242/jcs.238030

Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. / Pedicone, Ciara; Fernandes, Sandra; Dungan, Otto M.; Dormann, Shawn M.; Viernes, Dennis R.; Adhikari, Arijit A.; Choi, Lydia B.; De Jong, Ebbing P.; Chisholm, John D.; Kerr, William G.

In: Journal of cell science, Vol. 133, No. 5, 10.01.2020.

Research output: Contribution to journalArticle

Pedicone, C, Fernandes, S, Dungan, OM, Dormann, SM, Viernes, DR, Adhikari, AA, Choi, LB, De Jong, EP, Chisholm, JD & Kerr, WG 2020, 'Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis', Journal of cell science, vol. 133, no. 5. https://doi.org/10.1242/jcs.238030
Pedicone C, Fernandes S, Dungan OM, Dormann SM, Viernes DR, Adhikari AA et al. Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. Journal of cell science. 2020 Jan 10;133(5). https://doi.org/10.1242/jcs.238030
Pedicone, Ciara ; Fernandes, Sandra ; Dungan, Otto M. ; Dormann, Shawn M. ; Viernes, Dennis R. ; Adhikari, Arijit A. ; Choi, Lydia B. ; De Jong, Ebbing P. ; Chisholm, John D. ; Kerr, William G. / Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. In: Journal of cell science. 2020 ; Vol. 133, No. 5.
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