Critical Role of Microglia in Modulating Tau Proteostasis and Toxicity
Li Gan Gladstone Institutes, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, USA
Microglia mediate brain's innate immune response, which has emerged as a critical driving force in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Fronteotemporal dementia (FTD). One of the key pathogenic mechanisms shared by AD and a subset of FTD is the accumulation and propagation of toxic tau aggregates, which correlate well with cognitive decline and disease progression. The role of microglia in mediating tau propagation and toxicity remains unknown. We hypothesize that microglia play a critical role in turning non-toxic tau into toxic forms of tau to drive tau propagation and toxicity. In support of this hypothesis, we showed that co-culturing neurons with microglia significantly increase propagations of tau inclusions. More detailed analyses revealed that in the presence of mouse or human microglia tau fibrils are proteolytically cleaved and hyperacetylated, known to be highly pathogenic. Indeed, incubation of antibodies against acetylated tau protected against propagation of tau inclusions. To dissect the signaling pathways, we found that aggregated and mutant tau markedly activates NF-κB signaling in human iPSC-derived microglia and mouse primary microglia. Selective deletion of NF-κB signaling in transgenic mice expressing FTD mutant human tau protected against tau-mediated cognitive deficits and the spread of tau inclusions triggered by inoculation of tau fibrils. In contrast, constitutive activation of NF-kB in microglia resulted in cognitive deficits and enhanced tau propagation. Thus, inhibition of aberrant microglial activation could lead to new therapeutic strategies against tau-mediated neurodegeneration.
Supported by: NIA, NINDS, and Tau Consortium
Credits: None available.
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