Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease.
Chimeric Alzheimer mice
Human microglia
Lipid droplets
TREM2
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
23 07 2021
23 07 2021
Historique:
received:
22
02
2021
accepted:
13
07
2021
entrez:
24
7
2021
pubmed:
25
7
2021
medline:
11
1
2022
Statut:
epublish
Résumé
Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer's disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.
Sections du résumé
BACKGROUND
Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer's disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown.
METHODS
To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed.
RESULTS
Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE.
CONCLUSIONS
Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.
Identifiants
pubmed: 34301296
doi: 10.1186/s13024-021-00473-0
pii: 10.1186/s13024-021-00473-0
pmc: PMC8305935
doi:
Substances chimiques
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
50Subventions
Organisme : NIA NIH HHS
ID : RF1 AG048099
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056303
Pays : United States
Organisme : NIH HHS
ID : S10 OD010794
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066519
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG016573
Pays : United States
Organisme : NIH HHS
ID : S10 OD021718
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061895
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR025496
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Informations de copyright
© 2021. The Author(s).
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