Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission

Chan Chen, Ramhari Kumbhar, Hu Wang, Xiuli Yang, Kundlik Gadhave, Cyrus Rastegar, Yasuyoshi Kimura, Adam Behensky, Sumasri Kotha, Grace Kuo, Sruthi Katakam, Deok Jeong, Liang Wang, Anthony Wang, Rong Chen, Shu Zhang, Lingtao Jin, Creg J. Workman, Dario A.A. Vignali, Olga PletinkovaHongpeng Jia, Weiyi Peng, David W. Nauen, Philip C. Wong, Javier Redding-Ochoa, Juan C. Troncoso, Mingyao Ying, Valina L. Dawson, Ted M. Dawson, Xiaobo Mao

Research output: Contribution to journalArticlepeer-review

Abstract

The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain,and for AD and related Tauopathies, a therapeutic target.

Original languageEnglish (US)
Article number2303775
JournalAdvanced Science
Volume11
Issue number16
DOIs
StatePublished - Apr 24 2024

Keywords

  • Tau
  • Tau preformed fibrils
  • cell-to-cell transmission
  • lymphocyte-activation gene 3
  • receptor

ASJC Scopus subject areas

  • General Engineering
  • General Chemical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • General Materials Science
  • General Physics and Astronomy
  • Medicine (miscellaneous)

Fingerprint

Dive into the research topics of 'Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission'. Together they form a unique fingerprint.

Cite this