Abstract
INTRODUCTION
Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer’s disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.
METHODS
We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell–derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering.
RESULTS
We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering.
DISCUSSION
CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain.
Highlights
CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09.
CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism.
Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.
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This post is Copyright: Stephen P. Schauer,
Chang Hoon Cho,
Gloriia Novikova,
Gillie A. Roth,
Julie Lee,
Anup D. Sharma,
Alejandro R. Foley,
Carl Ng,
Philip Shen,
Meena Choi,
Taylur P. Ma,
Lilian Phu,
Hanna G. Budayeva,
Tommy K. Cheung,
Guita Lalehzadeh,
Jose Imperio,
Hai Ngu,
Ainhoa Etxeberria,
Yuxin Liang,
Mitchell G. Rezzonico,
Michelle Dourado,
Kevin Huang,
Zijuan Lai,
Martha Hokom,
Nikhil J. Pandya,
Dwight Newton,
Alyaa M. Abdel‐Haleem,
Pamela Chan,
Donna Lee,
Nardos G. Tassew,
Dewakar Sangaraju,
Deborah O’Connor,
Isidro Hötzel,
Kimberly L. Stark,
Carolina Chou,
Oded Foreman,
Amy Easton,
Kristin R. Wildsmith,
Gizette Sperinde,
Christopher M. Rose,
Brad A. Friedman,
Reina N. Fuji,
Robby M. Weimer,
William J. Meilandt,
Shraddha Sadekar,
Alicia A. Nugent,
Anne Biever | August 2, 2024