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 Pletinkova; Hongpeng 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

doi:10.1002/advs.202303775

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

Adv Sci (Weinh). 2024 Apr;11(16):e2303775. doi: 10.1002/advs.202303775. Epub 2024 Feb 7.

Authors

Chan Chen^{1

2}, Ramhari Kumbhar^{1

2}, Hu Wang^{1

2}, Xiuli Yang^{1

2}, Kundlik Gadhave^{1

2}, Cyrus Rastegar^{1

2}, Yasuyoshi Kimura^{1

2}, Adam Behensky^{1

2}, Sumasri Kotha^{1

2}, Grace Kuo^{1

2}, Sruthi Katakam^{1

2}, Deok Jeong^{1

2}, Liang Wang^{1

2}, Anthony Wang^{1

2}, Rong Chen^{1

2}, Shu Zhang^{1

2}, Lingtao Jin³, Creg J Workman⁴, Dario A A Vignali^{4

5

6}, Olga Pletinkova⁷, Hongpeng Jia⁸, Weiyi Peng⁹, David W Nauen⁷, Philip C Wong⁷, Javier Redding-Ochoa^{2

7}, Juan C Troncoso^{2

7}, Mingyao Ying^{2

10}, Valina L Dawson^{1

2

11

12

13}, Ted M Dawson^{1

2

12

13

14}, Xiaobo Mao^{1

2

15

16}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
³ Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
⁵ Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
⁶ Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
⁷ Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁸ Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁹ Department of Biology and Biochemistry, University of Houston, 3517 Cullen Blvd., Houston, TX, 77204, USA.
¹⁰ Hugo W. Moser Research Institute at Kennedy Krieger, 707 North Broadway, Baltimore, MD, 21205, USA.
¹¹ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA.
¹² Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹⁴ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹⁵ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA.
¹⁶ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.

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.

Keywords: Tau; Tau preformed fibrils; cell‐to‐cell transmission; lymphocyte‐activation gene 3; receptor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Disease Models, Animal
Humans
Lymphocyte Activation Gene 3 Protein*
Mice
Neurons* / metabolism
Tauopathies* / genetics
Tauopathies* / metabolism
Tauopathies* / pathology
tau Proteins* / genetics
tau Proteins* / metabolism

Substances

Antigens, CD
Lymphocyte Activation Gene 3 Protein
tau Proteins
Lag3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding