Tau is a protein found predominantly within the nerve cells, or neurons, of the brain. While it serves a normal function in healthy brain activity, tau exists in various distinct forms known as isoforms. These different versions of the tau protein are important for the brain’s proper functioning and are implicated in the development of several neurological diseases.
The Basic Tau Protein
The tau protein is a highly soluble and intrinsically disordered protein belonging to the microtubule-associated protein (MAP) family. It is primarily located within the axons of neurons, the long, slender projections that transmit electrical impulses to other cells. Tau’s main function is to stabilize microtubules, structural components within the cell that act like internal “railroad tracks” for transporting substances and maintaining cell shape. Tau proteins interact with tubulin to promote the assembly and stability of these microtubule structures, essential for neuronal function.
How Different Tau Isoforms Are Made
The term “isoforms” refers to different versions of the same protein, all originating from a single gene. In the case of tau, these isoforms are produced through alternative splicing of the MAPT gene. This process allows a single MAPT gene to produce multiple distinct tau protein isoforms by selectively including or excluding certain segments of its genetic code, known as exons, during protein synthesis.
Six main tau isoforms are found in the adult human brain, differing in size and structure. These variations arise from the alternative splicing of exons 2, 3, and 10. A key distinction among these isoforms is the number of microtubule-binding repeats (MTBRs) they contain. The two most common and functionally significant types are 3-repeat (3R) tau, which has three binding domains, and 4-repeat (4R) tau, which has an additional fourth binding domain due to the inclusion of exon 10.
The Diverse Roles of Tau Isoforms
The various tau isoforms, particularly the 3R and 4R forms, contribute to the precise and varied functions of neurons in a healthy brain. The ratio and specific expression of these isoforms are not uniform; they vary across different brain regions and at different stages of development. For instance, the shortest isoform, 0N3R, is primarily expressed during neurogenesis, while adult brains have a nearly equal ratio of 3R and 4R tau isoforms.
The differing structures of 3R and 4R tau influence their ability to bind to microtubules. The 4R tau isoforms, with their additional microtubule-binding repeat, exhibit a stronger binding affinity and promote faster and more efficient microtubule assembly compared to 3R tau isoforms. This diversity in binding characteristics allows tau isoforms to affect microtubule stability and dynamics in nuanced ways, important for the nervous system’s complex architecture and function.
Tau Isoforms in Neurodegenerative Diseases
When tau isoforms become dysfunctional, they detach from microtubules, misfold, and aggregate into insoluble clumps known as neurofibrillary tangles (NFTs). This abnormal tau accumulation is a hallmark pathology in various neurodegenerative conditions. In Alzheimer’s Disease (AD), tau tangles are a prominent feature alongside amyloid plaques, and both 3R and 4R tau isoforms are found within these tangles.
Beyond Alzheimer’s, a group of neurodegenerative diseases collectively known as “tauopathies” are characterized by tau pathology as their primary feature, often without amyloid pathology. These diseases include Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Pick’s Disease. In these tauopathies, the specific ratios or types of tau isoforms found in the tangles can differ, contributing to their distinct clinical presentations.
For example, in PSP and CBD, the tau aggregates predominantly consist of 4R tau isoforms. PSP is characterized by the destruction of protein filaments in nerve cells, leading to symptoms such as abnormal speech and balance impairment. CBD also exhibits neuronal loss and intracytoplasmic filamentous tau pathology, primarily composed of 4R tau. In contrast, Pick’s Disease is characterized by distinctive spherical inclusions called Pick bodies, which are primarily composed of hyperphosphorylated 3R tau isoforms. Understanding these isoform-specific pathologies is important for developing targeted therapies.