Microglia-based targets have received increased attention in neurodegenerative drug development. Among them, triggering receptor expressed on myeloid cells 2 (TREM2), a receptor on microglia, has been shown to be important for the activation of homeostatic microglia into a disease-associated state that displays neuroprotective features in Alzheimer’s disease. Here, we developed a quantitative systems pharmacology (QSP) to explore the most efficient way to modulate TREM2 activation, i.e. either to positively modulate TREM2 by direct activation or to block TREM2 shedding [3,4]. The model predicted that both mechanisms are comparable, but that blocking shedding is more efficient than directly activating TREM2 in obtaining the maximum pharmacodynamic effect on amyloid load reduction. The model also predicted that the response to TREM2 antibody depends on the microglial phenotype fractions present at the start of treatment.
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