BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Mar 2024
06 Mar 2024
Historique:
received:
10
02
2023
accepted:
16
02
2024
medline:
8
3
2024
pubmed:
7
3
2024
entrez:
6
3
2024
Statut:
epublish
Résumé
Genetic and experimental evidence suggests that Alzheimer's disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, sc/nRNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as DLAMs. Using macrophage sc/nRNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40/41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.
Identifiants
pubmed: 38448474
doi: 10.1038/s41467-024-46315-7
pii: 10.1038/s41467-024-46315-7
pmc: PMC10917780
doi:
Substances chimiques
Cholesterol
97C5T2UQ7J
Lipids
0
BHLHE40 protein, human
0
Homeodomain Proteins
0
Basic Helix-Loop-Helix Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2058Subventions
Organisme : NIA NIH HHS
ID : RF1 AG054011
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG081417
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG066757
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR004419
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL153712
Pays : United States
Organisme : NIH HHS
ID : S10 OD030463
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG058635
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2024. The Author(s).
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