Tau protein, in Alzheimer s disease

Gong C X, Liu F, Grundke-Iqbal I, et al. (2005). Post-translational modifications of tau protein in Alzheimer s disease. J. Neural Transmis. (Vienna, Austria), 112 813-838. 

Leclerc, S., Garnier, M., Hoessel, R. (2001) et al. Indirubins inhibit glycogen synthase kinase-3 3 and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer s disease. A property common to most cyclin-dependent kinase inhibitors. J. Biol. Chem., 276, 251-260. 

The study of metal containing proteins is a challenging task in proteomics. Metal containing proteins have been directly determined in separated protein bands in ID gel by LA-ICP-MS. In order to investigate the binding of Cu and Zn on tau protein isoforms as target proteins in Alzheimer s disease, enriched isotope tracers ( Cu and Zn) have been doped to the ID gel of separated tau protein isoforms after gel electrophoresis. Five bands in the ID gel were selected for LA-ICP-SFMS measurements (see Figure 9.25 a). Isotope ratio analyses were performed by... 

Among the structural proteins which are subject to GSK-3 regulation, the microtubule-associated protein tau is a prime target in Alzheimer s disease pathology. Tau binds to tubulin and promotes microtubule assembly and stability in a phosphorylation-dependent manner. The phosphorylation status of tau is balanced by antagonistic kinase and phosphate activities. Inappropriate hyperphosphorylation of tau is a key event in contributing to cytoskeletal abnormalities and tau pathology in Alzheimer s disease. When hyperphos-phorylated, tau s affinity for the microtubule is reduced and as a consequence tau dissociates from the microtubules. This leads to abnormal accumulation... 

Tolnay M, Probst A. Review tau protein pathology in Alzheimer s disease and related disorders. Neuropathol Appl Neurobiol 1999 25 171-187. 

Calcineurin is a serine/threonine protein phosphatase widely distributed in the brain, but its role in brain function remains unknown. It is critical for several important cellular processes including T-cell activation, and recent data indicate that it may be involved in hyperphosphorylation of tau in Alzheimer s disease (600, 601). The active site of native calcineurin contains zinc and iron metal ions and three metal-bound water molecules (602), one of which may be involved in nucleophilic attack on the substrate. Compound 119 (FK506, tacroli-... 

Neuroanatomical and neuropathological basis of Alzheimer s disease Histological features of Alzheimer s disease include neuritic plaques and neurofibrillary tangles (Boiler and Duyckaerts 1997). Neuritic plaques are composed of extracellular deposits of j8-amyloid protein and apolipoprotein E and are found primarily in neocortex. j8-amyloid is derived from an amyloid precursor protein, and is suspected to be a chief causal factor in Alzheimer s disease pathology (Samuel et al. 1997). Neurofibrillary tangles are clusters of protein fibers found in the cell body and composed of tau protein, which normally serves as a cytoskeletal element. Neurofibrillary tangles progress from entorhinal cortex to hippocampus, and then to neocortical areas. 

Fig. 10.9 Pathogenic factors acting on neuronal targets in Alzheimer s disease and the process of pharmacological treatment. ABP, amyloid 3-protein APP, ABP precursor protein CHO, choies-teroi NFT-Tau, neurofibriiiary tangie tau...

There is also interest in the involvement of the cytoskeleton in such degenerative diseases as Alzheimer s disease (see Chapter 14) which is characterized by tangles (paired helical filaments). It seems likely that one of the microtubule-associated proteins (tau protein) is an important component of the tangles found in Alzheimer s disease. 

Some processes involved in Alzheimer s disease. From the left mitochondrial dysfunction, possibly involving glucose utilization synthesis of protein tau and aggregation in filamentous tangles synthesis of amyloid 3 (A3) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. 

FIGURE 12-15. Another key finding in Alzheimer s disease is the pathological finding of another degenerative structure called neurofibrillary tangles made up of abnormally phosphorylated tau proteins. 

The microtubule-associated-protein tau is a component of the neurofibrillary tangles in Alzheimer s disease and a target of S100A1. PC 12 cells devoid of S100A1 were shown to be more resistant to A(3(25-35) peptide-mediated cell death and have lower levels of intracellular amyloid precursor protein (APP) (Zimmer et al., 2005). 

Alonso AD, Zaidi T, Novak M, Barra HS, Grundke-Iqbal I, Iqbal K. Interaction of tau isoforms with Alzheimer s disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J Biol Chem 2001 276(41) 37967-37973. 

The histopathological characteristics of the brain in Alzheimer s diseases (AD) are the presence of intraneuronal neurofibrillary tangles (NFTs), extraneuronal amyloid-rich senile plaques, and a massive loss of neurons of the telencephalon. Although amyloid proteins are unique to senile plaques, several components are common to both senile plaques and NFTs hyperphosphory-lated tau proteins, ubiquitin, a 1-antichymotrypsin, apolipoprotein E, heparan sulfate proteoglycans, and Al and Fe [29]. Recent reports on Al and Fe transport mechanisms and the relation between them in AD are reviewed below. 

Tau protein phosphorylated at threonine 181 in csf as a neurochemical taomarker in Alzheimer s disease original data and review of the literamre. J. Mol. Neurosci. 

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