A Guide To Tau Proteins & Tauopathies

Explore the essential role of Tau proteins in neuronal health and their impact in neurodegenerative diseases, unfolding the complexity behind their functions and dysfunctions.

1. Tau proteins, especially microtubule-associated protein tau (MAPT), are crucial for neuron structure maintenance.
2. They stabilize microtubules, which are integral for cell functions like division and neurotransmission.
3. In neurodegenerative diseases like Alzheimer's, tau proteins undergo abnormal changes, leading to neurofibrillary tangles.
4. Tau proteins are present in the brain and peripheral tissues, and their gene is located on chromosome 17.
5. Various neurodegenerative disorders, collectively called tauopathies, are characterized by abnormal tau protein accumulation.

The human gene that encodes for tau proteins is found on chromosome 17. Each tau protein is about 50-85 kilodaltons in size and has around 0.01% of the total brain proteins. Tau consists of many domains that are important for its function, including:

• The N-terminal domain (which contains four microtubule-binding repeats)
• The proline-rich region (which is located between the microtubule-binding domain and the C-terminus)
• The C-terminal domain (which has several phosphorylation sites).

Tau proteins are composed of six different isoforms, which are all encoded by a single gene. Their number of microtubule-binding domains distinguishes the six isoforms: three (termed "three-repeat tau" or "TRE"), four (termed "four-repeat tau" or "FRE"), and zero (termed "zero-repeat tau" or "ZRE").

While tau proteins are primarily found in the nervous system, they are also present in other tissues, such as the kidney and heart. In these tissues, tau plays a role in cell division and differentiation. By regulating these cellular processes, tau contributes to tissue development, maintenance, and repair. However, it is important to note that the abundance of tau in peripheral tissues is considerably lower compared to the nervous system. Mutations in the tau gene (MAPT) have been linked to a variety of diseases, including cancer. These mutations can disrupt the normal function of tau and potentially contribute to the development and progression of tumors.

Tauopathies are a group of neurodegenerative disorders characterized by the abnormal accumulation of tau protein aggregates in the brain. These diseases are often associated with cognitive decline, behavioral changes, and motor impairments. While several tauopathies have been identified, Alzheimer's disease stands as the most prevalent and well-known example.

Frontotemporal dementia (FTD) is a group of disorders characterized by the progressive degeneration of the frontal and temporal lobes of the brain. Some forms of FTD, particularly the behavioral variant, show prominent tau pathology. The accumulation of abnormal tau protein in brain cells contributes to the neurodegenerative process in FTD. This tau-related pathology predominantly affects behavior, personality, and language abilities. Individuals with FTD may exhibit changes in social behavior, such as disinhibition or apathy, emotional blunting, language difficulties (aphasia), and executive dysfunction. The specific symptoms can vary depending on the subtype of FTD and the regions of the brain primarily affected by tau pathology.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder characterized by the accumulation of tau protein in brain cells. It affects the basal ganglia, brainstem, and certain regions of the cortex. PSP primarily impairs movement control, leading to symptoms such as difficulties with balance, impaired eye movements (resulting in a characteristic gaze palsy), stiffness, and frequent falls. In addition to motor impairments, cognitive changes can occur in PSP, including problems with attention, executive functions, and language. The accumulation of tau protein in the affected brain regions contributes to the disruption of neuronal functioning, ultimately resulting in the observed clinical manifestations of PSP.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While primarily associated with the loss of dopamine-producing neurons, some cases of PD show the presence of abnormal tau protein aggregates, known as Parkinson's disease with tau pathology (PDTP). These tau-related abnormalities in PDTP can contribute to more severe motor and cognitive impairments compared to classical PD. Common motor symptoms of PD include resting tremors, bradykinesia, rigidity, and postural instability, while non-motor symptoms encompass cognitive decline, mood changes, sleep disturbances, and autonomic dysfunction. Understanding the role of tau pathology in PD and its interaction with other pathological features, such as alpha-synuclein aggregates, is an active area of research in unraveling the complex mechanisms underlying Parkinson's disease.

Alzheimer's disease and Parkinson's disease are both neurodegenerative disorders that cause cognitive decline and motor dysfunction. However, there are several key differences between these two diseases. Alzheimer's disease is characterized by the buildup of amyloid plaques and tangles made up of tau proteins. This leads to the death of neurons and the degeneration of brain tissue. Parkinson's disease is characterized by the aggregation of alpha-synuclein proteins. However, tau proteins can also be found in Lewy bodies, which are structures that are associated with Parkinson's disease. While both Alzheimer's disease and Parkinson's disease cause cognitive decline, the rate of decline is different. Alzheimer's disease typically causes a more gradual decline, while Parkinson's disease often causes a more rapid decline. Parkinson’s disease is treatable with medication and surgery. There is no cure for Alzheimer’s disease, but there are treatments available that can help to slow the progression of the disease.

Alzheimer's disease and frontotemporal dementia both cause cognitive decline. However, Frontotemporal dementia is characterized by tangles made up of tau proteins. However, these tangles primarily affect the frontal and temporal lobes of the brain, which are responsible for language and decision-making. While both Alzheimer's disease and frontotemporal dementia cause cognitive decline, the rate of decline is different. Frontotemporal dementia often causes a more rapid decline. There is no cure for Alzheimer’s disease or frontotemporal dementia, but there are treatments available that can help to slow the progression of the disease.

Individuals with Down syndrome, a genetic disorder caused by an extra copy of chromosome 21, often exhibit cognitive impairments and an increased susceptibility to early-onset Alzheimer's disease. In both conditions, there is an involvement of tau proteins, which form neurofibrillary tangles and contribute to neuronal dysfunction. The overexpression of the amyloid precursor protein (APP) due to the extra chromosome 21 in Down syndrome leads to the accumulation of amyloid-beta plaques, triggering tau pathology. This association sheds light on the cognitive deficits in Down syndrome and the higher risk of developing Alzheimer's-like dementia. Understanding the interplay between tau proteins, Down syndrome, and Alzheimer's disease can pave the way for targeted therapeutic approaches to improve the cognitive outcomes of individuals with Down syndrome.

A tau kinase is an enzyme that phosphorylates tau proteins by adding phosphate groups to specific sites on the tau molecule. This phosphorylation process regulates the normal function of tau in maintaining neuronal structure. However, dysregulation of tau kinases can lead to abnormal phosphorylation, promoting the formation of neurofibrillary tangles observed in tauopathies. Tau kinases such as GSK-3β, CDK5, MAPKs, and PKA have been identified, and understanding their role and dysregulation is crucial for developing therapeutic strategies aimed at mitigating tau pathology in neurodegenerative disorders.

A tau mutation is a change in the structure of the tau protein. These changes can make tau proteins more likely to break down and form tangles. Tau mutations are thought to be one of the causes of neurodegenerative diseases. Mutations in the tau gene can cause a variety of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. In these diseases, tau proteins become abnormally shaped and are no longer able to effectively stabilize microtubules. This leads to the loss of function of neurons and the degeneration of brain tissue.

Tau phosphorylation is the process by which enzymes add phosphate groups to tau proteins. This modifies the structure of the protein and can make it more stable. Phosphorylation can help to prevent neurodegenerative diseases. Hyperphosphorylated tau protein is a type of tau that has been phosphorylated to an excessively high level. This can lead to the formation of neurofibrillary tangles.

Tau is measured in order to determine the levels of this protein in the brain, which is crucial for diagnosing and tracking the progression of neurodegenerative diseases. Two main methods used for measuring tau are PET scans and post-mortem brain tissue analysis.

PET scans provide information about tau accumulation in the brain over time, allowing researchers to visualize and quantify tau pathology in living individuals. This imaging technique involves the use of a radioactive tracer that selectively binds to tau aggregates. By detecting the emitted radiation from the tracer, PET scans generate images reflecting the distribution and density of tau pathology.

Post-mortem brain tissue analysis, on the other hand, allows for the examination of tau levels at a specific point in time. Techniques like immunohistochemistry and immunofluorescence are employed to label and visualize tau protein and its aggregates in brain tissue samples obtained after an individual's death. This microscopic analysis provides insights into the presence and distribution of tau aggregates in specific brain regions.

Additionally, tau levels can be measured in cerebrospinal fluid (CSF). Techniques like ELISA (enzyme-linked immunosorbent assay) and western blotting can be employed to quantify tau protein in CSF or other biological samples. ELISA utilizes specific antibodies that selectively bind to tau protein, while western blotting involves separating proteins based on their molecular weight and detecting tau protein bands using antibodies.

If you have been diagnosed with a tau mutation, there is no specific treatment. However, there are treatments available that can help to slow the progression of the disease. These treatments include medications and lifestyle changes. Medications can help to improve symptoms and slow the progression of the disease. Lifestyle changes, such as exercise and a healthy diet, can also help to slow the progression of the disease. If you have a tau mutation, it is important to see a doctor regularly so that your condition can be monitored and treated if necessary.