Tau in Alzheimer disease and related tauopathies

Abstract

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

Fig. (1). A schematic representation of various pathological states of tau originating from normal brain tau and associated loss of normal and gain of toxic functions

Normal brain tau, which has a stoichiometry of 2–3 moles phosphate/mole of the protein, stimulates assembly of tubulin and stabilizes the structure of microtubules produced. During development, anesthesia as well as hypothermia, such as during hibernation, tau is transiently hyperphosphorylated. During development the level of brain tubulin is >4 mg/ml, the critical concentration required for its self-assembly into microtubules and the role of tau for this function is less critical. The hyperphosphorylation of tau during anesthesia and hypothermia, however, leads to a decrease in microtubule network and the associated functions. In AD brain a phosphorylation/dephosphorylation imbalance caused apparently by a decrease in protein phosphatase-2A activity leads to abnormal hyperphosphorylation of tau. This AD P-tau on one hand sequesters normal MAPs from microtubules and causes inhibition and disruption of microtubules. On the other hand, while the binding of AD P-tau to MAP1 or MAP2 results in amorphous aggregates, the binding to normal tau forms oligomers. Unlike normal tau, which is highly soluble, the tau oligomers formed with AD P-tau can be sedimented at 200,000 × g and self-assemble into PHF/SF in the form of neurofibrillary tangles.