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| Status |
Public on Aug 15, 2017 |
| Title |
TREM2 is a global regulator of microglia energetic and biosynthetic metabolism during steady state and in Alzheimer’s disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The most common form of senile dementia, Alzheimer’s disease (AD), is characterized by Aβ plaques and neurofibrillary tangles in the CNS. AD genetic studies have identified high-risk hypomorphic variants in TREM2, a myeloid cell surface receptor that enables concerted microglial responses to Aβ plaques and neuronal cell death, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes these responses is not known. Here, we demonstrate that TREM2 drives mTOR signaling, which maintains high ATP levels, supports biosynthetic pathways and suppresses AMPK phosphorylation and autophagy. In vitro, TREM2-deficient macrophages undergo dramatically increased autophagy and die in response to growth factor limitation or ER stress. Excessive autophagy is also evident in microglia from Trem2-/- 5XFAD mice and in post-mortem specimens from AD patients carrying TREM2 risk variants. Metabolic derailment, autophagy and cell death can be circumvented by engaging alternative energy production pathways. Thus, restoring microglial energetic and anabolic levels may be a future therapeutic avenue for TREM2-associated neurological disease.
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| Overall design |
Bone marrow-derived macrophages (BMDMs) from WT and Trem2–/– mice were cultured in either 0.5% or 10% LCCM overnight in complete RPMI. Some samples cells were stimulated with 10 ng/ml LPS for 4 hours.
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| Contributor(s) |
Ulland TK, Song W, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M |
| Citation(s) |
28802038 |
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| Submission date |
May 04, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Maxim N. Artyomov |
| E-mail(s) |
martyomov@pathology.wustl.edu
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| Organization name |
Washington University in St.Louis
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| Department |
Immunology&Pathology
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| Street address |
660 S. Euclid Avenue, Campus Box 8118
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| City |
St.Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (32)
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| Relations |
| BioProject |
PRJNA385524 |
| SRA |
SRP106492 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE98563_counts.txt.gz |
678.5 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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