Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

Alzheimer's disease cerebrospinal fluid chitinase‐3‐like protein 1 microglia pharmacodynamic biomarker triggering receptor expressed on myeloid cells 2

Journal

Alzheimer's & dementia : the journal of the Alzheimer's Association

ISSN: 1552-5279

Titre abrégé: Alzheimers Dement

Pays: United States

ID NLM: 101231978

Informations de publication

Date de publication:
01 Aug 2024

Historique:

revised: 22 03 2024

received: 21 12 2023

accepted: 25 03 2024

medline: 2 8 2024

pubmed: 2 8 2024

entrez: 1 8 2024

Statut: aheadofprint

Résumé

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. 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. 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. CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain. 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.

Identifiants

DOI: 10.1002/alz.13921 PMID: 39090679

pubmed: 39090679

doi: 10.1002/alz.13921

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : Genentech, Inc

Informations de copyright

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