Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy

Chao Wang, Li Fan, Rabia R. Khawaja, Bangyan Liu, Lihong Zhan, Lay Kodama, Marcus Chin, Yaqiao Li, David Le, Yungui Zhou, Carlo Condello, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Sue-Ann Mok, Jason E. Gestwicki, Ana Maria Cuervo, Wenjie Luo () and Li Gan ()
Additional contact information
Chao Wang: University of California, San Francisco
Li Fan: Brain and Mind Research Institute, Weill Cornell Medicine
Rabia R. Khawaja: Albert Einstein College of Medicine
Bangyan Liu: Brain and Mind Research Institute, Weill Cornell Medicine
Lihong Zhan: University of California, San Francisco
Lay Kodama: Brain and Mind Research Institute, Weill Cornell Medicine
Marcus Chin: University of California, San Francisco
Yaqiao Li: University of California, San Francisco
David Le: University of California, San Francisco
Yungui Zhou: University of California, San Francisco
Carlo Condello: University of California, San Francisco
Lea T. Grinberg: University of California, San Francisco
William W. Seeley: University of California, San Francisco
Bruce L. Miller: University of California, San Francisco
Sue-Ann Mok: Faculty of Medicine and Dentistry, University of Alberta
Jason E. Gestwicki: University of California, San Francisco
Ana Maria Cuervo: Albert Einstein College of Medicine
Wenjie Luo: Brain and Mind Research Institute, Weill Cornell Medicine
Li Gan: University of California, San Francisco

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-29552-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29552-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-29552-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().