Abstract
Unique microglial states have been identified in Alzheimer’s disease (AD) model mice and postmortem AD brains. Although it has been well documented that amyloid-β accumulation induces the alteration of microglial states, the relationship between tau pathology and microglial states remains incompletely understood because of a lack of suitable AD models. In the present study, we generated a novel AD model mouse by the intracerebral administration of tau purified from human brains with primary age-related tauopathy into App knock-in mice with humanized tau. Immunohistochemical analyses revealed that Dectin-1-positive disease-associated microglia were increased in the AD model mice after tau accumulation in the brain. We then performed single-nucleus RNA sequencing on the AD model mice to evaluate the differences in microglial states with and without tau propagation and accumulation. By taking advantage of spatial transcriptomics and existing single-cell RNA sequencing datasets, we showed for the first time that tau propagation and accumulation induce a disease-associated microglial phenotype at the expense of an age-related non-homeostatic counterpart (namely, white matter-associated microglia) in an AD model mouse brain. Future work using spatial transcriptomics at single-cell resolution will pave the way for a more appropriate interpretation of microglial alterations in response to tau pathology in the AD brain.
Significance Statement We generated a novel Alzheimer's disease model mouse showing humanized tau accumulation and propagation after amyloid beta accumulation. Immunohistochemical analyses revealed that disease-associated microglia were increased in the model mice after tau accumulation in the brain. Using single-cell RNA-seq and spatial transcriptomics, we showed for the first time that tau propagation and accumulation induce a disease-associated microglial phenotype at the expense of an age-related non-homeostatic counterpart in the model mouse brain.
Footnotes
The authors declare no conflict of interest.
All animal experiments were performed according to the animal experimental guidelines of RIKEN. This research was approved by the ethics committee of RIKEN and the Tokyo Metropolitan Institute for Geriatrics and Gerontology. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The single-cell RNA-seq and spatial transcriptomic datasets generated in the present study have been deposited in the Gene Expression Omnibus (GEO) repository under accession number GSE270389. Any additional data supporting the findings of this study are available from the lead contact upon request.
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