HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitro
Haage, Verena Claudia
;
Tuddenham, John F
;
Bautista, Alex
, et al.
bioRxiv,2024.
DOI:
10.1101/2024.10.11.617544
PubMed ID:
39416157
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Abstract: Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes1. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans2-6; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate7,8. Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1, LIPA and SCIN as DAMmarker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.
Keywords:
Disease-associated microglia (DAM) ;
in vitro model systems ;
human microglia ;
functional analysis
Purchased from AmBeed:
209783-80-2 ;
149647-78-9
Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors
Roth, Lukas
;
Gotsbacher, Michael P.
;
Codd, Rachel
J. Med. Chem.,2020,63(20):12116-12127.
DOI:
10.1021/acs.jmedchem.0c01541
PubMed ID:
32940035
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Abstract: Immobilized metal-ion affinity chromatog. (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target. This work examined the performance of Cu(II)-, Fe(III)-, Ga(III)-, Ni(II)-, or Zn(II)-IMAC resins to reversibly bind exptl. or clin. metalloenzyme inhibitors of Zn(II)-ACE1, Zn(II)-HDAC, Fe(II)/(III)-5-LO or Cu(II)-tyrosinase from a curated mixture (1-17). Each IMAC system gave a distinct selection profile. The Zn(II)-IMAC system selectively bound the thiol-containing Zn(II)-ACE1 inhibitors captopril and omapatrilat, and the Fe(III)-IMAC system selectively bound the Fe(II)/(III)-5-LO inhibitor licofelone, demonstrating a remarkable IMAC-metalloenzyme metal ion match. IMAC provides a simple, water-compatible platform, which could accelerate metalloenzyme inhibitor discovery.
Purchased from AmBeed:
209783-80-2 ;
112522-64-2 ;
76420-72-9 ;
81872-10-8 ;
76547-98-3
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