Tau Protein

Tau is a microtubule-associated protein that is important for cytoskeletal structure and intracellular transport. ^[1] Human tau is encoded by the MAPT gene on chromosome 17q21.31, whose exons 2, 3 and 10 are alternatively spliced to generate 6 isoforms ranging from 352 to 441 amino acids in the adult human brain. ^[2] Isoforms are named by their number of amino-terminal inserts (0N, 1N, 2N) and of carboxyl-terminal microtubule-binding repeats (3R or 4R), and tau is expressed predominantly in neurons, with lower expression in glia. ^[2] Tauopathies are a clinically and neuropathologically heterogeneous group of neurodegenerative disorders characterized by abnormal tau aggregates. ^[1] Tauopathies may be primary, or secondary when a second protein such as amyloid-beta is necessary for pathology, as in Alzheimer's disease, the most common tauopathy. ^[1] Primary tauopathies include Pick disease, corticobasal degeneration, progressive supranuclear palsy and argyrophilic grain disease, while chronic traumatic encephalopathy is an environmental tauopathy. ^[1] Mutations in MAPT can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), the clearest evidence that tauopathy plays a causal role in neurodegeneration. ^[3]

Physiologically, tau binds microtubules and is important for their assembly and stabilization, for proper axonal transport and for overall neuronal integrity. ^[4] In a pathological state tau becomes hyperphosphorylated, causing tau dysfunction that leads to synaptic impairment and degeneration of neurons. ^[5] Beyond phosphorylation, tau is also acetylated and proteolytically cleaved, and these modifications contribute to both its physiological and pathological functions. ^[2] Intracellular neurofibrillary tangles of hyperphosphorylated tau and extracellular plaques enriched in amyloid-beta are the two main pathological hallmarks of Alzheimer's disease. ^[2] The earliest, cellular phase of Alzheimer's disease happens in parallel with accumulating amyloid-beta, which induces the spread of tau pathology. ^[6] In Alzheimer's disease

In the A/T/N biomarker scheme, "T" is a tau biomarker (CSF phospho tau or tau PET), whereas CSF total tau is grouped with markers of neurodegeneration or neuronal injury ("N"). ^[8] The NIA-AA Research Framework defines Alzheimer's disease biologically using biomarkers of amyloid-beta deposition, pathologic tau and neurodegeneration [AT(N)], and is intended for research rather than routine clinical care. ^[9] A meta-analysis of 231 articles found that CSF total tau and phosphorylated tau were strongly associated with Alzheimer's disease and concluded that CSF total tau, phosphorylated tau, amyloid-beta 42 and neurofilament light should be used in clinical practice and research. ^[10] Second-generation tau-PET tracers with high affinity and selectivity for Alzheimer's tau pathology detect tau in the medial temporal lobe subregions affected in the earliest disease stages, and have revealed common spreading subtypes with greater interindividual variation than previously assumed.