LAG-3 may Serve as a Potential Therapeutic Target for Tau Protein Disorders

Recently, there was a publication by a research team. They found that Lymphocyte Activation Gene-3 (LAG-3) in neurons is a specific receptor for Tau Pre-formed Fibril (PFF) in the brain, which promotes the propagation of Tau PFF between neurons. In addition, they observed that if LAG-3 was knocked down in neurons, it significantly reduced the endocytosis of Tau PFF and decreased its propagation between neurons. This result also implies that LAG-3 may serve as a potential therapeutic target for AD and Tau protein disorders.

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Protein Aggregation in Neurodegenerative Diseases

Protein aggregation is a major pathological feature of degenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In AD and PD, for example, tau proteins and α-synuclein are altered in the pathological state, and further aggregated to form a propagating "seed" (e.g., PFF, which is also an aggregate of tau), which can enter the cell to induce intracellularly derived protein misfolding and aggregation and propagate between neurons by intercellular transmission, causing protein aggregates to persist to fibrillar and insoluble fiber morphologies. Interneuron propagation, which sustains the protein aggregates towards the morphology of PFF and insoluble fibers, and eventually protein deposits and tangles.

There have also been studies identifying some receptors associated with tau protein endocytosis and spreading, such as acetylheparan sulfate proteoglycan and low-density lipoprotein receptor-associated protein 1. However, these receptors are not specific for tau PFF.

Some researchers discovered back in 2016 that a cell surface receptor, LAG-3, can bind specifically to the PFF of α-synuclein, and that inhibiting LAG-3 inhibits the uptake of α-synuclein and reduces pathological aggregation of α-synuclein. On this basis, the researchers wondered whether LAG-3 could also bind specifically to tau PFF.

LAG-3 Binds Specifically to Tau PFF

In the latest study, the researchers first extracted AD-tau from the brains of AD patients, then obtained tau PFF using sonication, and investigated the specific binding of LAG-3 to tau PFF by a series of checkpoint assays.

• First, through cell surface binding assays, the researchers found that LAG-3 could bind to biotin-labeled tau PFF, but not to the biotin-labeled monomeric form of tau.
• Further, the researchers concluded that LAG-3 in neurons can bind specifically to biotin-labeled tau PFF and that biotin-labeled tau PFF binds preferentially to the D1 structural domain of the extracellular domain of LAG-3, as derived from a comparison of the KD differences between normal neurons in wild-type mice and neurons in wild-type mice lacking LAG-3 and biotin-labeled tau PFF.
• Next, the researchers explored whether LAG-3 is involved in the endocytosis of tau PFF. After binding tau PFF to the dye (which fluoresces red after endocytosis occurs), the researchers found that tau PFF fluoresces in wild-type mouse cortical neurons, whereas neurons lacking LAG-3 showed little fluorescent signal, and conversely, neurons overexpressing LAG-3 showed enhanced fluorescent signal. This suggests that LAG-3 is indeed involved in the endocytosis of tau PFF and that LAG-3 knockdown significantly inhibits its endocytosis.

The Role of LAG-3 in Tau PFF Neuron to Neuron Transmission

In addition to its direct interaction with tau protein aggregates, emerging evidence suggests that LAG-3 may play a crucial role in the intercellular transmission of pathological tau species between neurons. Tau propagation, the process by which misfolded tau proteins spread from one neuron to another, is believed to contribute to the progressive spread of tau pathology throughout the brain in tauopathies. Recent studies have implicated LAG-3 in mediating tau neuron-to-neuron transmission, providing further insight into the pathophysiological mechanisms underlying disease progression.

To observe the role of LAG-3 in tau PFF interneuron propagation, the researchers performed a microfluidic device to simulate interneuron propagation. The results revealed that LAG-3 plays a key role in tau PFF interneuron propagation.

• In neuronal devices lacking LAG-3, the amount of insoluble tau protein was reduced.
• On the contrary, in neuronal devices overexpressing LAG-3, the insoluble tau protein content was significantly increased.

From these results, it is clear that LAG-3 can bind specifically to tau PFF and promote the propagation of tau PFF between neurons, so LAG-3 may serve as a potential therapeutic target for tau protein disorders.

LAG-3 as a Therapeutic Target for AD

The identification of LAG-3 as a key player in tau pathology has positioned this immune checkpoint molecule as a promising therapeutic target for AD and related tauopathies. Targeted modulation of LAG-3 activity holds the potential to intervene at multiple stages of tau-mediated neurodegeneration, from the initial aggregation of tau proteins to the propagation of pathological tau species throughout the brain.

After injecting LAG-3 antibodies into cortical neurons, researchers found that LAG-3 antibodies not only significantly blocked the binding of LAG-3 to tau PFF, but also reduced the transmission of tau PFF between neurons.

Fig. 1 Binding of LAG-3 to LAG-3 antibody significantly reduces Tau PFF binding and endocytosis, leading to delayed propagation of pathology and toxicity.¹

• One promising avenue for LAG-3-targeted therapeutics is the development of monoclonal antibodies that selectively bind to and modulate LAG-3 function. By blocking the interaction between LAG-3 and tau fibrils, these antibodies may disrupt the propagation of tau pathology and attenuate neurodegeneration in tauopathies.
• Additionally, small molecule inhibitors of LAG-3 signaling pathways represent another viable approach for therapeutic intervention, offering the potential for targeted modulation of LAG-3 activity in the context of neurodegenerative diseases.

Creative Biolabs is at the forefront of LAG-3-targeted therapeutics development, leveraging cutting-edge technologies and innovative approaches to harness the therapeutic potential of LAG-3 modulation in neurodegenerative diseases.

Reference

1. Chen, Chan, et al. "Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission." Advanced Science (2024): 2303775.

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