puc-header

TREM2 Regulates Microglial Cholesterol Metabolism Upon Chronic Phagocytic Challenge

85 Pages Posted: 3 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Alicia A. Nugent

Alicia A. Nugent

Denali Therapeutics

Karin Lin

Denali Therapeutics

Bettina Van Lengerich

Denali Therapeutics

Steve Lianoglou

Denali Therapeutics

Laralynne Przybyla

Denali Therapeutics

Sonnet S. Davis

Denali Therapeutics

Ceyda Llapashtica

Denali Therapeutics

Junhua Wang

Denali Therapeutics

Do Jin Kim

Denali Therapeutics

Dan Xia

Denali Therapeutics

Anthony Lucas

Denali Therapeutics

Sulochanadevi Baskaran

Denali Therapeutics

Patrick C.G. Haddick

Denali Therapeutics

Melina Lenser

Denali Therapeutics

Timothy K. Earr

Denali Therapeutics

Ju Shi

Denali Therapeutics

Jason C. Dugas

Denali Therapeutics

Benjamin J. Andreone

Denali Therapeutics

Todd Logan

Denali Therapeutics

Hilda O. Solanoy

Denali Therapeutics

Hang Chen

Denali Therapeutics

Ankita Srivastava

Denali Therapeutics

Suresh B. Poda

Denali Therapeutics

Pascal E. Sanchez

Denali Therapeutics

Ryan J. Watts

Denali Therapeutics

Thomas Sandmann

Denali Therapeutics

Giuseppe Astarita

Denali Therapeutics

Joseph W. Lewcock

Denali Therapeutics

Kathryn M. Monroe

Denali Therapeutics

Gilbert Di Paolo

Denali Therapeutics

More...

Abstract

Loss of function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer’s disease (AD) risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting techniques with RNA sequencing and lipidomics, we found that wildtype microglia acquire a disease-associated microglia transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia maintain phagocytic activity of myelin debris, but are incompetent at clearing myelin lipids, including cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase was also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding was replicated in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it was rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.

Keywords: microglia, Lipid metabolism, lipid dysregulation, cholesterol, cholesteryl ester, TREM2, ApoE, myelin, neurodegeneration, Alzheimer's disease, phagocytosis

Suggested Citation

Nugent, Alicia A. and Lin, Karin and Van Lengerich, Bettina and Lianoglou, Steve and Przybyla, Laralynne and Davis, Sonnet S. and Llapashtica, Ceyda and Wang, Junhua and Kim, Do Jin and Xia, Dan and Lucas, Anthony and Baskaran, Sulochanadevi and Haddick, Patrick C.G. and Lenser, Melina and Earr, Timothy K. and Shi, Ju and Dugas, Jason C. and Andreone, Benjamin J. and Logan, Todd and Solanoy, Hilda O. and Chen, Hang and Srivastava, Ankita and Poda, Suresh B. and Sanchez, Pascal E. and Watts, Ryan J. and Sandmann, Thomas and Astarita, Giuseppe and Lewcock, Joseph W. and Monroe, Kathryn M. and Di Paolo, Gilbert, TREM2 Regulates Microglial Cholesterol Metabolism Upon Chronic Phagocytic Challenge (August 29, 2019). NEURON-D-19-01269. Available at SSRN: https://ssrn.com/abstract=3444596 or http://dx.doi.org/10.2139/ssrn.3444596
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Alicia A. Nugent

Denali Therapeutics ( email )

United States

Karin Lin

Denali Therapeutics

United States

Bettina Van Lengerich

Denali Therapeutics ( email )

United States

Steve Lianoglou

Denali Therapeutics ( email )

United States

Laralynne Przybyla

Denali Therapeutics ( email )

United States

Sonnet S. Davis

Denali Therapeutics ( email )

United States

Ceyda Llapashtica

Denali Therapeutics

United States

Junhua Wang

Denali Therapeutics ( email )

United States

Do Jin Kim

Denali Therapeutics ( email )

United States

Dan Xia

Denali Therapeutics

United States

Anthony Lucas

Denali Therapeutics ( email )

United States

Sulochanadevi Baskaran

Denali Therapeutics ( email )

United States

Patrick C.G. Haddick

Denali Therapeutics ( email )

United States

Melina Lenser

Denali Therapeutics ( email )

United States

Timothy K. Earr

Denali Therapeutics ( email )

United States

Ju Shi

Denali Therapeutics ( email )

United States

Jason C. Dugas

Denali Therapeutics ( email )

United States

Benjamin J. Andreone

Denali Therapeutics

United States

Todd Logan

Denali Therapeutics ( email )

United States

Hilda O. Solanoy

Denali Therapeutics ( email )

United States

Hang Chen

Denali Therapeutics

United States

Ankita Srivastava

Denali Therapeutics

United States

Suresh B. Poda

Denali Therapeutics ( email )

United States

Pascal E. Sanchez

Denali Therapeutics ( email )

United States

Ryan J. Watts

Denali Therapeutics

United States

Thomas Sandmann

Denali Therapeutics ( email )

United States

Giuseppe Astarita

Denali Therapeutics ( email )

United States

Joseph W. Lewcock

Denali Therapeutics ( email )

United States

Kathryn M. Monroe

Denali Therapeutics ( email )

United States

Gilbert Di Paolo (Contact Author)

Denali Therapeutics ( email )

United States

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
943
Downloads
64