Soluble TREM2 proteoforms: biomarker discovery and biological characterization for alzheimer's disease

Overview

This research program addresses a critical gap in Alzheimer's disease (AD) diagnostics and biology by characterizing the heterogeneous pool of soluble TREM2 (sTREM2) proteoforms. TREM2 is a transmembrane receptor expressed by microglia, the brain's resident immune cells, and plays a central role in regulating neuroimmune responses in AD. While sTREM2 levels in cerebrospinal fluid (CSF) are known to fluctuate with disease progression, the underlying biology has remained unclear. This program reveals that the sTREM2 pool is composed of three distinct proteoforms generated through alternative splicing and proteolytic cleavage, each potentially carrying different diagnostic and functional significance. The work combines biomarker development with mechanistic neuroscience to advance both detection and understanding of AD.

Technical specifications

Key capabilities and findings:

• Identification of three distinct sTREM2 proteoforms derived from TREM2 gene splicing, including the full-length membrane receptor and two secreted forms lacking a transmembrane domain
• Custom polyclonal antibodies capable of detecting individual sTREM2 proteoforms in human brain tissue and CSF
• Discovery that all sTREM2 proteoforms exhibit cell non-autonomous actions, blocking long-term potentiation through a GABA_A receptor-sensitive mechanism, indicating direct influence on synaptic function
• Quantitative assays to measure each proteoform species in individuals with mild cognitive impairment (MCI), AD, and healthy controls
• Evidence that TREM2 transcripts are elevated in the AD brain, supporting a role in disease-associated immune activation

Research objectives:

• Determine the proteoform composition of CSF sTREM2 and how its secretion is regulated during disease progression
• Evaluate cell-autonomous and non-cell-autonomous actions of sTREM2 on neural cell types
• Assess whether individual sTREM2 proteoforms offer improved sensitivity as biomarkers compared to total sTREM2 measurement

Technology readiness level

The program is at an advanced preclinical research stage. Proof-of-concept data has been generated demonstrating the existence of distinct sTREM2 proteoforms, the development of proteoform-specific antibodies, and the functional impact of sTREM2 on synaptic plasticity. Ongoing and future validation will focus on quantifying sTREM2 proteoforms in well-characterized human CSF cohorts spanning MCI, AD, and healthy controls, and on establishing whether proteoform-level measurement provides superior diagnostic sensitivity over existing sTREM2 assays. The custom antibody tools and biomarker assay framework are positioned for translational refinement and potential licensing or co-development with diagnostic industry partners.