Tau is a highly soluble protein found predominantly within the neurons of the central nervous system, where it helps maintain cellular structure. It is especially abundant in the axon, the long projection neurons use to transmit electrical signals. Phosphorylation is a common biological process involving the addition of a phosphate group to a protein, regulating its function and activity. Abnormal changes to this regulatory process involving Tau are a defining characteristic of several devastating brain diseases.
Tau Protein’s Stabilizing Role
Tau is classified as a microtubule-associated protein (MAP), describing its primary function within the neuron. Neurons rely on the cytoskeleton, an internal scaffolding system where microtubules—hollow, tube-like filaments—form the main tracks. Microtubules are essential for maintaining the neuron’s shape and structural integrity, particularly along the axon.
They also serve as internal “railroad tracks” for the movement of materials between the cell body and the synapse. Tau proteins bind directly to the microtubules, promoting their assembly and preventing them from falling apart, which stabilizes the tracks and regulates cargo transport.
How Phosphorylation Regulates Tau
Phosphorylation is a dynamic, reversible process that acts as a molecular switch controlling Tau’s interaction with microtubules. This modification involves adding a phosphate group to specific amino acid sites on the Tau protein, changing its electrical charge and shape. Specialized enzymes called kinases add these phosphate groups, while phosphatases perform the removal, known as dephosphorylation.
This constant addition and removal allows the neuron to precisely adjust microtubule stability. For instance, increased phosphorylation temporarily loosens Tau’s grip, allowing the microtubule network to be quickly remodeled for synaptic plasticity and growth. The balance between kinases and phosphatases dictates when and where the tracks are stabilized or disassembled, demonstrating that phosphorylation is a normal and necessary biological tool.
The Shift to Pathological Hyperphosphorylation
The shift from normal, regulated phosphorylation to a disease state occurs when Tau becomes pathologically hyperphosphorylated, meaning it accumulates an excessively high number of phosphate groups. While normal Tau has approximately two to three phosphate groups attached, hyperphosphorylated Tau can carry three to four times that amount. This uncontrolled addition is often due to an imbalance where the activity of specific kinases is dramatically increased, or the activity of phosphatases is significantly decreased.
This excessive chemical modification causes a profound change in the Tau protein’s three-dimensional structure, leading it to misfold. The misfolded protein detaches completely from the microtubules, stripping them of their stabilizing support. Without Tau’s stabilizing presence, the microtubule tracks begin to destabilize and eventually disintegrate, severely compromising the structural integrity of the neuron.
The detached, hyperphosphorylated Tau proteins then start to self-aggregate, clumping together in the neuron’s cytoplasm. These insoluble clumps are known as Neurofibrillary Tangles (NFTs), which are a defining characteristic of Tau-related diseases. This cascade of hyperphosphorylation, detachment, microtubule collapse, and aggregation creates a toxic environment that contributes to the neuron’s eventual demise.
Linking Tau Aggregation to Neurodegeneration
The accumulation of hyperphosphorylated Tau and the subsequent formation of NFTs are directly linked to the progressive decline seen in neurodegenerative diseases. The structural failure of the microtubule network, due to Tau’s detachment, causes the collapse of the neuron’s internal transport system. This breakdown prevents essential nutrients and signaling molecules from reaching their destinations, leading to impaired communication between neurons.
The physical presence of the NFTs further disrupts the internal cellular environment, interfering with normal cellular processes and contributing to synaptic dysfunction. The combined effect of transport failure and intracellular disruption ultimately leads to the death of the affected neurons, a process called neurodegeneration. Cognitive decline in patients, such as memory loss and dementia, often correlates strongly with the extent and location of NFT deposition in the brain.
This pathology is most widely recognized in Alzheimer’s Disease (AD), where NFTs are one of the two main pathological hallmarks. Tau hyperphosphorylation and aggregation also define a group of disorders collectively called tauopathies, including Chronic Traumatic Encephalopathy (CTE) and Progressive Supranuclear Palsy (PSP).