UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia

Piers, TM; Cosker, K; Mallach, A; Johnson, GT; Guerreiro, R; Hardy, J; Pocock, JM; (2019) A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia. FASEB Journal 10.1096/fj.201902447R. Green open access

[thumbnail of Piers_et_al-2019-The_FASEB_Journal.pdf]
Preview
Text
Piers_et_al-2019-The_FASEB_Journal.pdf - Published Version

Download (751kB) | Preview

Abstract

Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.

Type: Article
Title: A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1096/fj.201902447R
Publisher version: https://doi.org/10.1096/fj.201902447R
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biology, Cell Biology, Life Sciences & Biomedicine - Other Topics, Alzheimer's disease, glycolysis, metabolism, microglia, PROLIFERATOR-ACTIVATED RECEPTOR, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PPAR-GAMMA, CELLS, EXPRESSION, PFKFB3, GLYCOLYSIS, METABOLISM, PROMOTES
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation
UCL > Provost and Vice Provost Offices > VP: Health
UCL > Provost and Vice Provost Offices > VP: Health > Translational Research Office
URI: https://discovery.ucl.ac.uk/id/eprint/10089469
Downloads since deposit
98Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item