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Review
. 2022 Apr 2;79(4):219.
doi: 10.1007/s00018-022-04225-1.

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Jinming Han  1 , Violeta Chitu  2 , E Richard Stanley  2 , Zbigniew K Wszolek  3 , Virginija Danylaité Karrenbauer #  4   5 , Robert A Harris #  6
Affiliations
Review

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Jinming Han et al. Cell Mol Life Sci. .

Abstract

Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Colony stimulating factor-1 receptor; Huntington’s disease; Multiple sclerosis; Parkinson’s disease.

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Conflict of interest statement

ZKW serves as PI or Co-PI on Biogen, Inc. (228PD201), Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), and Neuraly, Inc. (NLY01-PD-1) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research. VDK Biogen (recipient of grant and scholarship, PI for project sponsored by); Novartis (Scientific Advisory board member, recipient of scholarship and lecture honoraria); Merc (Scientific Advisory Board member, recipient of lecture honoraria), Neuro Vigil (Scientific Advisory Board member). VDK has received financial support from Stockholm County Council (Grant ALF 20160457), Biogen (recipient of grant and scholarship, PI for the project sponsored by Biogen); Novartis (Scientific Advisory Board member, recipient of scholarship and lecture honoraria) and Merck (Scientific Advisory Board member, recipient of lecture honoraria).

Figures

Fig. 1
Fig. 1
CSF-1R signaling pathways and the effects of CSF-1R inhibitors. CSF-1 and IL-34 share a common receptor, CSF-1R. After binding to the CSF-1R, a cascade of downstream signaling molecules is activated, including those involved in the PI3K-AKT, ERK1/2 and JAK/STAT signaling pathways, promoting cellular proliferation, survival and differentiation. PLX3397 (Pexidartinib) and PLX5622 are the most widely used CSF-1R inhibitors, with favorable tolerability profiles. Treatment with PLX3397, or PLX5622, causes effective depletion of microglia. PLX3397 also inhibits C-KIT, PDGFRα and FLT3. Consequently, in clinical practice, the broader effects of PLX3397 may cause adverse effects, including hair discoloration and hepatotoxicity. PLX5622 is a novel CSF-1R inhibitor with a higher selectivity. (-) indicate inhibitor-induced reduction in signaling through the respective pathways
See this image and copyright information in PMC

References

    1. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–845. doi: 10.1126/science.1194637. - DOI - PMC - PubMed
    1. Prinz M, Jung S, Priller J. Microglia biology: one century of evolving concepts. Cell. 2019;179(2):292–311. doi: 10.1016/j.cell.2019.08.053. - DOI - PubMed
    1. Sierra A, Paolicelli RC, Kettenmann H. Cien anos de microglia: milestones in a century of microglial research. Trends Neurosci. 2019;42(11):778–792. doi: 10.1016/j.tins.2019.09.004. - DOI - PubMed
    1. Eyo UB, Wu LJ. Microglia: lifelong patrolling immune cells of the brain. Prog Neurobiol. 2019;179:101614. doi: 10.1016/j.pneurobio.2019.04.003. - DOI - PMC - PubMed
    1. Hagemeyer N, Hanft KM, Akriditou MA, Unger N, Park ES, Stanley ER, Staszewski O, Dimou L, Prinz M. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 2017;134(3):441–458. doi: 10.1007/s00401-017-1747-1. - DOI - PMC - PubMed

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