Tau proteins are found primarily within the brain’s nerve cells, or neurons. These proteins maintain the structural integrity of brain cells. Their proper function supports overall brain health and activity.
The Normal Function of Tau
In a healthy brain, tau proteins interact with microtubules. Microtubules are tiny internal scaffolds or ‘railroad tracks’ within neurons, extending along axons. These tracks transport nutrients, signaling molecules, and other materials throughout the neuron.
Tau proteins stabilize microtubules, acting like ties that hold these ‘railroad tracks’ in place and ensuring efficient cellular transport. This stabilization helps neurons maintain their shape, grow, and conduct signals effectively. Properly functioning tau proteins help maintain the neuron’s complex internal organization.
Tau Protein Malfunction and Tangles
When tau proteins malfunction, hyperphosphorylation occurs, attaching excessive phosphate groups to the protein. Normal tau has two to three phosphate groups; in diseased states, this number can increase significantly. This over-attachment changes the tau protein’s shape and properties.
This altered structure causes tau to detach from microtubules, disintegrating the neuron’s internal transport system. Once detached, abnormally phosphorylated tau proteins clump together. They aggregate into insoluble, thread-like neurofibrillary tangles (NFTs) inside neurons. These tangles disrupt cellular functions and are a hallmark of several neurodegenerative conditions.
Associated Neurological Conditions
Diseases characterized by abnormal tau tangle accumulation are called “tauopathies.” They result from the progressive buildup of misfolded tau proteins within brain cells, leading to neurodegeneration and cognitive decline. While many older individuals develop some tangles with age, a greater number in specific brain regions is associated with disease.
Alzheimer’s disease (AD) is the most recognized tauopathy, featuring neurofibrillary tangles as one of two primary pathological features in the brain, alongside amyloid plaques. Their presence and spread correlate with the severity of cognitive impairment and memory loss in AD. Chronic Traumatic Encephalopathy (CTE) is another neurodegenerative condition linked to tau pathology, occurring after repeated head trauma. In CTE, hyperphosphorylated tau accumulates in a distinctive pattern, often around small blood vessels in the cortex.
Frontotemporal Dementia (FTD) is also a group of tauopathies primarily affecting the brain’s frontal and temporal lobes. FTD can manifest as changes in behavior, personality, or language, depending on the brain regions affected by tau accumulation. Other less common tauopathies include Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Pick’s disease (PiD), each characterized by distinct patterns of tau aggregation.
Detecting and Studying Abnormal Tau
Scientists and clinicians use advanced methods to detect and study abnormal tau. Positron Emission Tomography (PET) scans are an imaging technique for this purpose. During a tau PET scan, a radioactive tracer is injected. This tracer binds specifically to tau tangles in the brain, allowing their presence and distribution to be visualized.
Another method analyzes cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. A lumbar puncture (spinal tap) collects a sample of this fluid. Levels of phosphorylated tau (e.g., p-tau181, p-tau217, p-tau231) can be measured in the CSF. Elevated levels of these tau forms can indicate tau pathology in the brain, aiding diagnosis and research into disease progression.
Therapeutic Approaches Targeting Tau
Current research explores strategies to address tau-related diseases, focusing on various points in the tau pathology pathway. One approach aims to prevent the hyperphosphorylation of tau. This involves developing drugs that inhibit kinases, enzymes responsible for adding phosphate groups to tau. Reducing excessive phosphorylation aims to keep tau attached to microtubules and prevent its aggregation.
Another strategy focuses on clearing existing tau aggregates in the brain. Immunotherapy, for example, uses antibodies to recognize and remove pathological tau species. These antibodies can target and break down existing tangles, improving neuronal function and reducing neurodegeneration.
Scientists investigate therapies to stabilize microtubules, even if tau has detached. This approach aims to maintain neuronal structural integrity and transport functions independently of tau’s normal stabilizing role. Researchers also explore methods to inhibit the spread of pathological tau between cells, aiming to slow disease progression.