Current Understanding of Neurodegenerative Diseases Associated With the Protein Tau

Abstract

The primary tauopathies are a group of neurodegenerative diseases in which tau is believed to be the major contributing factor of the neurodegenerative process. In the primary tauopathies, there is a disassociation between tau, a microtubule associated protein, and microtubules, as a result of tau hyperphosphorylation. This disassociation between tau and microtubules results in tau fibrillization and inclusion formation, and microtubule dysfunction. There are different clinical syndromes associated with different primary tauopathies, and some clinical syndromes can be associated with multiple primary tauopathies. Hence, while some clinical syndromes are highly specific and almost diagnostic of a primary tauopathy, many are not, making it difficult to diagnose a primary tauopathy. Recently, radioligands that bind to tau and can be combined with positron emission tomography to detect fibrillary tau antemortem have been developed, although preliminary data suggest that these ligands may not be very sensitive in detecting tau associated with many of the primary tauopathies. Another recent advancement in the field is evidence demonstrating that tau may show similar properties to prions although infective transmission has not been demonstrated. There have been a few clinical trials targeting tau and microtubule dysfunction, although none have had any disease modifying effects. Understanding tau biology is critical to the development of pharmacologic agents that could have disease modifying effects on the primary tauopathies.

Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-43

“…In many of the NDs discussed previously, accumulation of tau contributes to disease in some capacity, with AD and FTLD variants (FTLD-17) implicating tau as a primary driver of disease 15,16,148 . In addition to AD and FTLD, several other NDs fall under the tauopathy classification: Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and others (reviewed in 149 ). These tauopathies can be further subcategorized by their expression of tau repeat domains, known as 3R tau and 4R tau, where the 3R isoforms arise from the omission of exon 10 of the tau gene (MAPT), while 4R isoforms include exon 10 (see Figure 4).…”

Tau Imaging in Neurodegenerative Diseases Using Positron Emission Tomography

“…This could possibly explain the variation in tau inclusion morphology and cellular specificity. Tauopathies, as a result, may be subdivided into disorders with inclusions made predominantly of 3R- or 4R-tau or a combination of both [ 8 ]. A brief molecular pathological classification of tauopathies is summarised in Table 1 .…”

Transcellular Spreading of Tau in Tauopathies

“…The list of tauopathies also contains Pick disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Gerstmann–Straussler–Scheinker disease, British dementia, Danish dementia, Guam Parkinsonism–dementia complex, tangle‐only dementia, white‐matter tauopathy with globular glial inclusions, and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP) . These pathologies are clinically diverse, ranging from progressive gait instability and gaze palsy, which is suggestive of PSP, to the loss of memory, which is associated with AD …”

“…[1] These pathologies are clinically diverse, ranging from progressive gait instability and gaze palsy,w hich is suggestive of PSP,t ot he loss of memory,w hich is associated with AD. [2] Ta ui samicrotubule-associated protein that is encoded by the MAPT gene on human chromosome1 7q21.31;i tp lays a role in the assembly and stabilisation of microtubules, which is essential for axonal transport. [3] Traditionally considered an intracellularp rotein, taui sa lso secreted in the cerebrospinal fluid (CSF), with increased levels in AD, in which it is used for confirmation of the clinical diagnosis.…”