Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. NFTs also are present in numerous other diseases known collectively as tauopathies. Little is known about their exact relationship to the different pathologies, but it is typically recognized that tauopathy is an important factor in the pathogenesis of several neurodegenerative diseases. NFTs consist primarily of a misfolded, hyperphosphorylated microtubule-associated protein known as tau, which abnormally polymerizes into insoluble filaments within cells. Under the electron microscope, these polymers of tau are seen to take two basic forms: paired helical filaments (PHFs) and straight filaments. These basic types of tau filaments can vary structurally, especially in different tauopathies. The filaments bundle together to form the neurofibrillary tangles that are evident under the light microscope. Classical NFTs are located within the neuronal cell body, although it is now recognized that abnormal, filamentous tau occurs also in neuronal dendrites and axons (referred to as neuropil threads) and the dystrophic (abnormal) neurites that surround neuritic Abeta plaques. Mature NFTs in cell bodies can have a torch-like or globose appearance, depending on the type of neuron involved. When tangle-containing neurons die, the tangles can remain in the neuropil as extracellular "ghost tangles".
Formation The precise mechanism of tangle formation is not completely understood. Tau protein normally binds to microtubules in cells, where it contributes to the formation and stabilization of these important components of the cytoskeleton. In the tauopathies, tau molecules are hyperphosphorylated and they fold into the wrong shape; in this deviant state they cause other tau molecules to misfold and stick to one another, eventually forming abnormal filaments. The misfolded tau molecules appear to act as seeds that transform other tau molecules to the abnormal state, thereby multiplying and spreading in the brain by a prion-like mechanism. The role of hyperphosphorylation in this process is uncertain. One possibility is that hyperphosphorylation reduces the normal binding of tau to microtubules, freeing the protein to self-assemble into polymers, but as of 2024, Michel Goedert and colleagues stated that "It is unknown if phosphorylation is necessary and/or sufficient for the assembly of tau into filaments in the brain". These authors also note that filamentous tau in NFTs is marked by other posttranslational modifications that could influence its properties in disease. In any case, hyperphosphorylation and misfolding of tau are well-established characteristics of NFTs that likely are important in the development of tauopathies. Three different maturation states of NFTs have been defined using anti-tau and anti-ubiquitin immunostaining. At stage 0 there are morphologically normal pyramidal cells showing diffuse or fine granular cytoplasmic staining with anti-tau antibodies (in other words, the cells appear to be healthy with minimal presence of aberrant tau); at stage 1 some delicate, elongated inclusions are stained by antibodies to tau (these are early tangles); stage 2 is represented by the classic appearance of NFTs as seen with anti-tau immunostaining; stage 3 is exemplified by ghost tangles (tangles outside of cells where the host neuron has died), which are characterized by a reduced immunostaining for tau but marked immunostaining for ubiquitin. In this sequence of events, the abnormal phosphorylation of tau occurs before the appearance of ubiquitin immunoreactivity. Once formed, NFTs appear to last for a long time in the brain, possibly remaining for many years after the death of the neurons in which they are formed. Ghost tangles can become immunoreactive with antibodies to other proteins in the extracellular environment, such as Abeta.
Causes
Genetics In adult humans there are 6 different types ("isoforms") of tau protein. The different tau isoforms range from 352 to 441 amino acids in length, and they influence the type of neurofibrillary pathology that is present in different tauopathies. An important segment of tau that regulates its binding to microtubules and also its anomalous self-assembly into fibrils is the repeat domain that consists of stretches of recurring amino acids; the repeat domain in tau contains either 3 or 4 Repeats (forming what are called "3R tau" and "4R tau"). There are also two different inserts in the amino terminal part of tau, whose presence or absence - along with either 3 or 4 repeats - define the 6 tau isoforms. In some tauopathies, including progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease, the intracellular inclusions consist of 4R tau; in Pick disease the inclusions consist of 3R tau, and in Alzheimer's disease both 3R tau and 4R tau are involved in the formation of neurofibrillary tangles. A healthy ratio of 3R tau to 4R tau (which normally is approximately 1:1 in the adult human brain) appears to be important in preventing tauopathy. In addition to these variations in normally expressed tau isoforms, missense mutations and mutations that affect the splicing of the genetic message for tau are associated with various tauopathies. In 1998, mutations in the MAPT gene were linked to a type of frontotemporal dementia with Parkinsonism; in the brains of affected patients, abnormal tau filaments were found in both neurons and glial cells. As of 2023, 65 different mutations had been identified that are involved in neurodegenerative tauopathies.
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