Tau has been the subject of study since its discovery in 1975. Its physiological function is to bind tubulin and stabilize microtubules; in this way it supports cell differentiation, polarization, and other processes involving the cytoskeleton. The pathogenic mechanism of tau in Alzheimer’s disease is less established. Recent hypotheses favor trans-synaptic propagation of a pathologic aggregate, leading eventually to microtubule breakdown and neurodegeneration.
Tau is primarily an intracellular protein, though recent evidence shows that it is also actively secreted. Histopathologically, aggregation of hyperphosphorylated tau into tangles and similar deposits occurs broadly across AD, frontotemporal dementia, and other neurodegenerative diseases. In AD, neurofibrillary pathology follows a stereotypical pattern that correlates well with the degree of dementia and forms the basis for staging the disease at autopsy. Genetically, however, mutations in the human tau gene MAPT only cause FTD, not AD.
As AD develops, tau is thought to change subsequent to Aβ, although the connection between the two is unclear. In human cerebral spinal fluid (CSF), tau levels become abnormal years after Aβ levels do, and in experimental models Aβ-induced toxicity requires the presence of tau. In the human brain, six tau isoforms are expressed from a single gene by alternative splicing, resulting in proteins with either three or four microtubule binding repeats; some pathogenic mutations shift the 4R/3R ratio of the healthy brain. In AD, tau undergoes post-translational changes including ubiquitination, oxidation, nitration, acetylation, proteolytic cleavage, and glycation, but it is unclear which are causes and which are consequence of the disease process.
In mature neurons most tau protein occurs in axons; missorting of tau toward the somatodendritic compartment is an early sign of neurodegeneration in AD mouse models. Mouse models of pathogenic tau mutations show tau aggregation, toxicity, neuronal loss, and behavioral deficits. CSF tau levels are a leading biomarker for AD. PET tracers are in early clinical development and are expected to accelerate drug development directed at tau, which is in its infancy.
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