Tau Accumulation Induces Microglial State Alterations in Alzheimer's Disease Model Mice
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 <i>App</i> 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 nonhomeostatic 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.
Authors
- Daisuke Motooka (ORCID: https://orcid.org/0000-0002-4616-9608)
- Daisuke Okuzaki (ORCID: https://orcid.org/0000-0002-4552-783X)
- Ryo Fujioka
- Yukio Matsuba
- Takaomi C. Saido (ORCID: https://orcid.org/0000-0003-1970-6903)
- Shigeo Murayama (ORCID: https://orcid.org/0000-0001-9709-5242)
- Shoko Hashimoto (ORCID: https://orcid.org/0000-0002-5778-4884)
- Naomi Mihira
- Masataka Kikuchi (ORCID: https://orcid.org/0000-0002-9562-841X)
- Hiroshi Kiyama (ORCID: https://orcid.org/0000-0001-5963-046X)
- Kenichi Nagata (ORCID: https://orcid.org/0000-0001-8377-7197)
- Daisuke Joho (ORCID: https://orcid.org/0009-0008-5623-0266)
- Hiroki Sasaguri (ORCID: https://orcid.org/0000-0003-2550-9156)
- Yu‐Chen Liu (ORCID: https://orcid.org/0000-0002-2750-0182)
- Misaki Sekiguchi
Institutions
- Chiba University (JP)
- Shiga University of Medical Science (JP)
- Shiga University (JP)
- RIKEN Center for Brain Science (JP)
- Center for Children (US)
- Pioneer (Japan) (JP)
- Innovation Research Center (US)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Child Development Center (QA)
- Shijonawate Gakuen University (JP)
- Nagoya University (JP)
- Niigata University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- eNeuro
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1523/eneuro.0260-24.2024
- Citations
- 8
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.98
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Osaka Medical Research Foundation for Intractable Diseases
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Research Institute for Microbial Diseases, Osaka University