Work

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

Year: 2022

Type: article

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.

Source: Nature Communications

DOI: 10.1038/s41467-022-29552-6

Authors: 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, Li Gan

Institutions: Gladstone Institutes, University of California, San Francisco, Weill Cornell Medicine, Albert Einstein College of Medicine, University of Alberta

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,890

Funders: Gladstone Institutes, Weill Cornell Medical College, University of California, San Francisco, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

Awards: Investigating the role of microRNAs in microglia in a mouse model of Alzheimerâs Disease, Linking tau proteostasis with neuronal activity in FTD, Understanding Alzheimer's Disease in the Context of the Aging Brain, Essential roles of DAP12 in tau metabolism and inflammation in Alzheimer's disease, Medical Scientist Training Program, Autophagy in aging: testing geroscience in Alzheimer's disease, G5844706375, Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging, Pharmaceutical Sciences and Pharmacogenomics, Tau acetylation in Alzheimer's disease, Bronx-Einstein Training in Teaching and Research (BETTR), an IRACDA program, Maladaptive antiviral pathways in Alzheimer's disease, Molecular Chaperones and Small Molecules, New Approaches to Dementia Heterogeneity, Molecular mechanisms in progranulin deficient frontotemporal dementia

OpenAlex ID: W4223521725

FWCI: 40.67

Cites: 93

Cited by: 333

Related to: 10