A cell therapy to restore Trem2 function in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. E.g., loss-of-function of the microglial gene Trem2 render microglia dysfunctional and causes an early-onset neurodegenerative syndrome and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant model of Alzheimer’s disease. Microglial replacement using bone-marrow cells combined with PLX5622 in Trem2 wildtype and Trem2 knockout mice.