Tau protein is a normal component found within the brain, particularly in neurons, where it maintains cellular structure and function. However, in certain neurological conditions, this protein can undergo changes that lead to the formation of abnormal clumps called neurofibrillary tangles. Understanding these tangles and their impact on brain health is important for comprehending neurodegenerative disorders. These protein aggregates represent a significant area of scientific investigation due to their observed presence in affected brain tissue.
The Role of Tau Protein
Tau protein normally supports the internal scaffolding of neurons by interacting with structures called microtubules. Microtubules are like internal railways within neurons, responsible for transporting nutrients, vesicles, and other essential cellular components from the cell body down to the axon terminals. Tau helps to stabilize these microtubules, ensuring their proper assembly and maintaining their structural integrity, which is necessary for efficient transport and overall neuronal health.
There are various forms of tau protein, known as isoforms. The precise way tau binds to microtubules is influenced by a balance of enzymes called kinases and phosphatases, which add or remove phosphate groups to the tau protein. This phosphorylation helps regulate tau’s activity and its ability to interact with microtubules, allowing for the dynamic nature of these cellular transport systems.
Formation of Neurofibrillary Tangles
Formation of neurofibrillary tangles begins with an abnormal process called hyperphosphorylation. This involves an excessive addition of phosphate groups to tau, often by specific kinases like GSK3 and CDK5. When tau becomes hyperphosphorylated, it loses its normal ability to bind to and stabilize microtubules.
Once detached from microtubules, these hyperphosphorylated tau proteins become prone to clumping together. They aggregate into insoluble structures, initially forming “pretangles” within the neuron. Over time, these pretangles develop into paired helical filaments (PHF) or straight filaments, which then intertwine to form the larger, twisted protein fibers known as neurofibrillary tangles. This aggregation can also exhibit “seeding” activities, where abnormal tau can induce normal tau to misfold and aggregate, contributing to the spread of pathology.
Impact on Brain Function
Neurofibrillary tangles detrimentally affect neuronal health and overall brain function. The detachment of tau from microtubules and its subsequent aggregation directly disrupts the microtubule network. This disruption impairs axonal transport, hindering the movement of vital nutrients, proteins, and organelles along the neuron’s axon. Impaired transport can lead to a buildup of waste products and a lack of necessary components at the synapses, where neurons communicate.
Such cellular damage can result in neuronal dysfunction and, eventually, neuronal death. The widespread degeneration of neurons and their connections contributes to the cognitive and memory problems observed in neurodegenerative conditions. While it was once thought that the presence of tangles inevitably led to gross physiological alterations and cell death, more recent research suggests that tangle-bearing neurons might still be functionally integrated in circuits, at least in some contexts. However, the overall accumulation and spread of these tangles are correlated with increased neurodegeneration and cognitive decline.
Associated Neurodegenerative Conditions
Tau neurofibrillary tangles define several neurodegenerative diseases, collectively known as tauopathies. Alzheimer’s disease (AD) is the most recognized condition with prominent tau pathology. In AD, abnormally hyperphosphorylated tau forms neurofibrillary tangles within neurons, and these tangles are found alongside extracellular amyloid-beta plaques. The progression of tau pathology in AD correlates with the severity of cognitive decline.
Other tauopathies also feature tau tangles. These include Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Pick’s disease. Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is another tauopathy, often caused by mutations in the tau gene itself, which can lead to abnormal tau hyperphosphorylation and aggregation. While the specific patterns of tau pathology can differ across these conditions, the presence of these abnormal tau aggregates remains a common pathological hallmark.