Tau protein, a microtubule-associated protein, is widely distributed in the central nervous system and plays a crucial role in maintaining and regulating neuronal morphology and function. In neurodegenerative diseases, abnormal aggregation of Tau protein forms neurofibrillary tangles, disrupting neuronal structure and function, leading to neuronal death and driving disease progression. Investigating the role of Tau protein in neurodegenerative diseases and the mechanisms underlying its abnormal aggregation is of great significance for developing new diagnostic methods and therapeutic strategies.

The Critical Role of Tau Protein in the Neuronal Cytoskeleton

Neurons are complex cells whose functions and structures rely on the dynamic reorganization of the cytoskeleton. The cytoskeleton is composed of microfilaments, microtubules, and intermediate filaments. Microfilaments resist tension, microtubules maintain cell shape and participate in cargo transport, while intermediate filaments anchor organelles. Tau protein, a key microtubule-associated protein in neurons, binds to microtubules in axons, promoting their assembly and preventing depolymerization to enhance stability. Tau’s function is finely regulated by post-translational modifications, particularly phosphorylation, which reduces its affinity with microtubules and modulates their dynamics—an essential process for healthy neuronal function.

https://doi.org/10.1002/cmdc.202400180

Figure 1. Tau protein's role in microtubule stability and transport

Structural Features of Tau Protein

Tau protein consists of four main domains: the N-terminal projection domain, proline-rich region, microtubule-binding domain (MBD), and C-terminal region. The N-terminal domain interacts with other cytoskeletal components and cell membranes, contributing to axonal stability. The proline-rich region contains phosphorylation sites that regulate neural signaling and intracellular signal transduction. The MBD determines Tau's binding affinity to microtubules, while the C-terminal region complements MBD to maintain microtubule stability and function. Alternative splicing generates six Tau isoforms, differing in N-terminal inserts (0N, 1N, 2N) and MBD repeats (3R or 4R), resulting in functional variations, particularly in microtubule-binding capacity.

https://doi.org/10.1002/cmdc.202400180

Figure 2. Six Tau isoforms generated by alternative splicing

Tau Protein and Neurodegenerative Diseases

Tau protein plays a vital role in normal neuronal function, but its dysfunction can lead to neurodegenerative diseases.

• Tau Protein in Alzheimer's Disease (AD)

AD, the most common neurodegenerative disease in the elderly, is characterized by abnormal Tau phosphorylation. Phosphorylated Tau detaches from microtubules, aggregates into neurofibrillary tangles, and disrupts neuronal structure and function, causing memory loss and cognitive impairment. The accumulation of amyloid-beta (Aβ) is another hallmark of AD. Studies suggest a strong link between Tau pathology and Aβ buildup. In early AD, Aβ plaques form between neurons, triggering inflammation and oxidative stress, which promote Tau phosphorylation and aggregation. In turn, Tau aggregates may enhance Aβ toxicity, creating a vicious cycle that drives AD progression.

https://doi.org/10.7150/ijbs.57078

Figure 3. Interaction of Aβ and Tau in AD

• Tau Protein in Parkinson's Disease (PD)

PD, the second most common neurodegenerative disease, is primarily characterized by the abnormal aggregation of α-synuclein (α-syn) into Lewy bodies, leading to the progressive loss of dopaminergic neurons in the substantia nigra. Emerging evidence suggests that Tau protein also contributes to PD pathology. Research by Pan L. et al. revealed that Tau interacts with α-syn, accelerating its aggregation. Pre-formed fibrils (PFFs) of mixed Tau and α-syn exhibit stronger propagation activity than α-syn PFFs alone, inducing mitochondrial and synaptic dysfunction as well as neurotoxicity. Autopsy studies of PD patients further show Tau and α-syn co-localized within Lewy bodies.

https://doi.org/10.1093/brain/awac171

Figure 4. Heatmap of pS129 pathology scores in mouse brains injected with different PFFs.

pS129 is a phosphorylation site on α-syn and a marker of α-syn aggregation. The heatmap shows the distribution and severity of α-syn pathology across brain regions in mice injected with α-syn PFFs or mixed Tau/α-syn PFFs. Redder areas indicate more severe pathology, with mixed Tau/α-syn PFFs causing broader and more severe α-syn pathology.

• Tau Protein in Huntington’s Disease (HD)

HD is a neurodegenerative disease caused by mutations in the huntingtin (HTT) gene, characterized by motor dysfunction, cognitive decline, and psychiatric symptoms. Although Tau phosphorylation is not a hallmark of HD, abnormal Tau phosphorylation and aggregation have been observed in late stages of the disease. Mutant huntingtin protein (mHtt) may disrupt Tau regulation, leading to its phosphorylation and aggregation. Additionally, altered 4R/3R Tau isoform ratios in the cortex and striatum of HD patients suggest mis-splicing of Tau is linked to HD pathology.

Summary

Tau protein plays a critical role in microtubule stability and neuronal function, with its dysfunction implicated in neurodegenerative diseases like AD, PD, and HD. To support research into Tau mechanisms and related diseases, we offer a wide range of high-quality Tau products, including wild-type, mutant, and phosphorylated Tau proteins, Tau PFFs, Tau stable cell lines, and p-tau antibodies, to fully meet the diverse needs of basic research and drug development.

Reference

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2. Yang J, Zhi W, Wang L. Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review[J]. Molecules, 2024, 29(12): 2812. https://doi.org/10.3390/molecules29122812

3. Zhang H, Wei W, Zhao M, et al. Interaction between Aβ and tau in the pathogenesis of Alzheimer's disease[J]. International journal of biological sciences, 2021, 17(9): 2181. https://doi.org/10.7150/ijbs.57078

4. Pan L, Li C, Meng L, et al. Tau accelerates α-synuclein aggregation and spreading in Parkinson’s disease[J]. Brain, 2022, 145(10): 3454-3471. https://doi.org/10.1093/brain/awac171

5. Singh S, Khan S, Shahid M, et al. Targeting Tau in Alzheimer’s and Beyond: Insights into Pathology and Therapeutic Strategies[J]. Ageing Research Reviews, 2024: 102639. https://doi.org/10.1016/j.arr.2024.102639