Mechanistic description
TREM2 microglial receptors can be engineered with synthetic recognition domains to selectively bind and clear cross-seeded protein aggregates while sparing monomeric forms. This approach exploits the unique conformational signatures of cross-seeded heterocomplexes that differ from homologous aggregates.
Evidence for (4)
TREM2 variants significantly modify risk across multiple neurodegenerative diseases
Engineered TREM2 constructs can be designed to recognize specific protein conformations
TREM2 activation promotes microglial phagocytosis of protein aggregates
Evidence against (5)
TREM2 deficiency can actually reduce some forms of neurodegeneration by decreasing neuroinflammation
TREM2 activation may promote rather than clear certain protein aggregates in some contexts
Engineered immune receptors often lose specificity and cause off-target effects