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Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism
Stephen P Schauer1, Chang Hoon Cho2, Gloriia Novikova3
1Department of Translational Medicine, Genentech, Inc., South San Francisco, California, USA.
Summary
New biomarkers, CSF chitinase-3-like protein 1 (CHI3L1) and soluble TREM2 (sTREM2), reflect microglial TREM2 agonism in Alzheimer's disease. These can monitor drug activity in clinical trials.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are investigated as Alzheimer's disease therapeutics.
- Pharmacodynamic (PD) biomarkers are crucial for clinical trials to confirm drug activity and optimize dosing.
Purpose of the Study:
- To identify and validate fluid PD biomarkers for TREM2 agonists.
- To assess the correlation between biomarker changes and microglial responses.
Main Methods:
- Multi-omic analyses of non-human primate brain and CSF.
- In vitro studies using human induced pluripotent stem cell-derived microglia.
- Immunoassay validation of candidate biomarkers.
- Immunostaining to assess microglial proliferation and clustering.
Main Results:
- CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) identified as PD biomarkers for the TREM2 agonist hPara.09.
- TREM2 agonist treatment led to reduced sTREM2 and elevated CHI3L1 in brain and CSF.
- Biomarker changes correlated with transient microglial proliferation and clustering.
Conclusions:
- CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism.
- These biomarkers can be utilized in clinical settings to monitor TREM2 activity in the brain.
