Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.

The microtubule-associated protein is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated from AD brain cytosol (AD P-) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35°C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six isoforms into tangles of PHF and straight filaments, and the microtubule binding domains͞repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that self-assembles by association of the microtubule binding domains͞repeats and that the abnormal hyperphosphorylation promotes the self-assembly of into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

Microtubule-associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical filaments in neurons undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P-tau) in a nonsaturable fashion, forming large tangles of filaments 3.3 +/- 0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P-tau alone, are made up of filaments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD P-tau to aggregate with normal tau and prevents tangle formation. AD P-tau disassembles microtubules assembled from normal tau and tubulin. These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the degeneration of the affected neurons in AD.

The microtubule assembly-promoting activity of different pools of tau protein isolated from Alzheimer disease (AD) and control brains and the effect of dephosphorylation on this activity were studied. Tau isolated from a 2.5% perchloric extract of AD brain had almost the same activity as that obtained from control brain, and this activity did not change fitly on dephosphorylation. Abnormally phosphorylated tau (AD P-tau) isolated from brain homogenate of AD patients had little activity, and upon dephosphorylation with alkaline phospbatase, its activity increased to approximately the same level as the acid-soluble tau. Addition of AD P-tau to a mixture of normal tau and tubulin inhibited microtubule assembly. AD P-tau bound to normal tau but not to tubulin. These studies suggest that the abnormal phosphorylation of tau might be responsible for the breakdown of microtubules in affected neurons in AD not only because the altered protein has little microtubule-promoting activity but also because it interacts with normal tau, making the latter unavailable for promoting the assembly of tubulin into microtubules.In the brains of patients with Alzheimer disease (AD), the cytoskeleton is progressively disrupted and displaced by the appearance of bundles of paired helical filaments (PHF), which are composed mainly ofhyperphosphorylated forms of tau protein (1, 2). Unlike normal tau, which contains two or three phosphate groups, the soluble hyperphosphorylated tau from AD brain (AD P-tau) contains 5-9 mol of phosphate per mol of the protein (3). Levels of tau are severalfold higher in AD than in the age-matched control brains, and this increase is in the form of the abnormally phosphorylated tau (4). Neurons with neurofibrillary tangles of PHF lack microtubules, and microtubule assembly from brain cytosol in the absence of an added polycation, DEAE-dextran, is not observed (5). The reason for this disruption might therefore be some alteration in either tau or other microtubuleassociated proteins. In AD brain, tau can be isolated from different pools: (i) a cytosolic fraction, (ii) abnormally phosphorylated tau that is not polymerized into PHF and sediments at 200,000 x g, and (iii) as a component of PHF. To understand the role of the abnormal phosphorylation of tau in microtubule disruption in AD brain, we studied the ability of the normal cytosolic tau and the AD P-tau to bind to tubulin and to promote microtubule assembly and investigated the effect of alkaline phosphatase treatment of tau on microtubule assembly. The studies described in this paper suggest that the abnormal phosphorylation of tau is a likely cause of the breakdown of the microtubule system in AD because the AD P-tau does not bind to tubulin and inhibits the in vitro assembly ofnormal tau and tubulin into microtubules. The altered tau inhibits microtubule assembly, probably through its binding to normal tau, making the latter unavailable for interaction with tubulin.

Alzheimer disease (AD) and related tauopathies are histopathologically characterized by a specific type of slow and progressive neurodegeneration, which involves the abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. This hallmark, called neurofibrillary degeneration, is seen as neurofibrillary tangles, neuropil threads, and dystrophic neurites and is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the non-fibrillized, abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau, which can be generated by catalysis of several different combinations of protein kinases, also promotes its misfolding, decrease in turnover, and self-assembly into tangles of paired helical and or straight filaments. Some of the abnormally hyperphosphorylated tau ends up both amino and C-terminally truncated. Disruption of microtubules by the non-fibrillized abnormally hyperphosphorylated tau as well as its aggregation as neurofibrillary tangles probably impair axoplasmic flow and lead to slow progressive retrograde degeneration and loss of connectivity of the affected neurons. Among the phosphatases, which regulate the phosphorylation of tau, protein phosphatase-2A (PP2A), the activity of which is down-regulated in AD brain, is by far the major enzyme. The two inhibitors of PP-2A, I1PP2A and I2PP2A, which are overexpressed in AD, might be responsible for the decreased phosphatase activity. AD is multifactorial and heterogeneous and involves more than one etiopathogenic mechanism.