Cell autonomous microglia defects in a stem cell model of frontotemporal dementia

Abstract

AbstractNeuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring theMAPTIVS10+16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered thatMAPTIVS10+16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors fromMAPTIVS10+16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observedin vitrowere recapitulated in human brain tissue and cerebrospinal fluid fromMAPTmutations carriers. Together, our findings thatMAPTIVS10+16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutic strategies.