Tau is a protein in the brain that performs specialized functions. Proteins often undergo modifications that can alter their activity, and one common modification is phosphorylation. Phosphorylation involves the addition of a phosphate group to an amino acid residue within a protein, a process catalyzed by enzymes called protein kinases. This modification can change a protein’s shape, activating or deactivating it, thereby affecting its overall function. When a phosphate group is added to the tau protein, it becomes “phospho-tau,” a modified form whose phosphorylation state influences its solubility, location, and interactions.
The Tau Protein’s Normal Function
Under healthy conditions, the tau protein maintains the internal structure of neurons, the brain’s primary cells. Tau is known as a microtubule-associated protein (MAP) because it binds to and stabilizes microtubules. Microtubules are like tiny tracks within neurons, forming part of the cell’s cytoskeleton and acting as a transport system. They are responsible for guiding nutrients, organelles, and other molecules throughout the neuron, from the cell body to the ends of the axon and back. This stability and transport function is important for proper neuronal communication and overall brain health.
How Phospho-Tau Contributes to Brain Diseases
While tau phosphorylation is a normal process that supports cytoskeletal structure, an increase in tau phosphorylation, known as hyperphosphorylation, reduces tau’s ability to bind to microtubules. When tau detaches from microtubules, it destabilizes the neuronal cytoskeleton. This unbound tau then begins to clump together, forming abnormal aggregates inside neurons. These aggregates are initially called paired helical filaments (PHFs) and eventually develop into larger structures known as neurofibrillary tangles (NFTs).
Neurofibrillary tangles disrupt the neuron’s internal transport system, hindering the movement of essential nutrients and molecules along microtubules. This disruption can lead to synaptic dysfunction and the eventual death of brain cells. While neurofibrillary tangles are a hallmark of Alzheimer’s disease, the presence of soluble, highly phosphorylated tau species may be more directly linked to synaptic problems and cell loss. The number of NFTs in the neocortex correlates with the severity of cognitive decline in Alzheimer’s.
Phospho-tau also plays a role in other neurodegenerative conditions, collectively known as tauopathies. These conditions include some frontotemporal dementias, progressive supranuclear palsy, and corticobasal degeneration. In these diseases, abnormal tau phosphorylation, altered tau levels, or tau gene mutations contribute to toxic tau inclusions. The aggregation of tau can also affect mitochondrial function and induce endoplasmic reticulum stress, further contributing to neuronal damage.
Identifying Phospho-Tau in the Body
Scientists and clinicians use various methods to detect and measure phospho-tau as a biomarker for neurodegenerative diseases. One common approach involves analyzing cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. Specific isoforms of phospho-tau, such as p-tau181, p-tau217, and p-tau231, are measured in CSF. Elevated levels of these phospho-tau variants in CSF are associated with Alzheimer’s disease pathophysiology.
Positron Emission Tomography (PET) imaging is another diagnostic tool. This technique uses radioactive tracers that bind to tau tangles in the brain, allowing visualization and quantification of abnormal tau accumulation in living individuals. While CSF p-tau measures soluble forms of tau and can indicate early tau changes, tau-PET imaging provides information on the anatomical distribution of tau pathology and is strongly associated with cognitive decline and reduced cortical thickness. Comparisons between CSF and PET biomarkers show that while they both capture aspects of tau pathology, they may provide different, yet complementary, information about disease progression.
Strategies for Addressing Phospho-Tau
Research explores therapeutic strategies to reduce or prevent abnormal phospho-tau accumulation. Immunotherapy, a prominent approach, uses antibodies to target and clear pathological tau aggregates. Both active immunization (stimulating the body’s own immune system to produce antibodies) and passive immunization (administering pre-made antibodies) are being investigated. These antibodies are designed to recognize specific forms of tau, including hyperphosphorylated, aggregated, or conformationally altered tau, and facilitate their removal.
Other strategies focus on modulating the enzymes that control tau phosphorylation. Inhibitors of kinases like glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), which are implicated in abnormal tau phosphorylation, have shown promise in preclinical studies. Similarly, enhancing the activity of protein phosphatases, such as protein phosphatase 2A (PP2A), could help dephosphorylate tau. Researchers are also exploring ways to enhance the brain’s natural clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, to degrade misfolded tau proteins. While these approaches offer hope for disease-modifying treatments, many are in early development or clinical trials, and challenges remain in developing specific and effective interventions.