Neurofibrillary tangle protein

Abreo K, Abreo F, Sella ML, Jain S (1999) Aluminum enhances iron uptake and expression of neurofibrillary tangle protein in neuroblastoma cells. J Neurochem 72 2059-2064... 

Aluminium and iron may share important biological pathways (Cannata et al. 1984, 1991, Can-NATA and Diaz L6pez 1991). Both are transported by transferrin (Trapp 1983, Martin 1986). Human serum transferrin released AP when the pH varied from pH 7.4 (Fatemi et al. 1991). The ubiquitous iron-storage protein, ferritin formed complexes with aluminium in the livers and brains of rats fed AICI3 for 1 year (Fleming and Joshi 1987). Ferritin isolated from the brains of patients who died of Alzheimer s disease contained more aluminium and more iron than that from age-matched controls. In neuroblastoma cells, aluminium enhanced iron uptake and expression of neurofibrillary tangle protein (Abreo et al. 1999). 

Goedert, M., Spillantini, M.G., Jakes, R., Rutherford, D., Crowther, R.A. (1989). Multiple isoforms of human microtubule-associated protein tau Sequences and localization in neurofibrillary tangles of Alzheimer s disease. Neuron 3, 519-526. 

The pathologic hallmarks of the disease in the brain include neurofibrillary tangles and neuritic plaques made up of various proteins, which result in a shortage of the neurotransmitter acetylcholine. These are primarily located in brain regions involved in learning, memory, and emotional behaviors such as the cerebral cortex, hippocampus, basal forebrain, and amygdala.11... 

Neurofibrillary tangles are intracellular and consist of abnormally phosphorylated tau protein which is involved in microtubule assembly. Tangles interfere with neuronal function... 

Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25 402-405, 2000. 

There is considerable evidence that defective homeostasis of redox-active metals, i.e. iron and copper, together with oxidative stress, contributes to the neuropathology of AD. The characteristic histology of AD is the deposition of both Ap, as neurotic plaques (Figure 18.12a), and of the protein tau, as neurofibrillary tangles NFT (Figure 18.12b), predominantly in the cerebral cortex and hippocampus. 

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. 

As illustrated in the diagram below, domain swapping can also result in indefinite polymerization to form linear supramolecular structures. These may correspond to present-day polymers of proteins such as microtubules, or they may represent abnormal structures, like the straight and paired-helical filaments in the neurofibrillary tangles observed in the brain tissue of those afflicted with Alzheimer s disease. 

Neurofibrillary tangles, aluminum associate with, 36 416-417 Neuromodulin, 46 449 Neuromuscular blocking agents, 36 7 Neuron-specific calcium sensor (NCS) proteins, 46 457... 

One theory of the pathogenesis of Alzheimer s disease proposes that increased production or decreased secretion of the Ap peptides leads to accumulation of these peptides. A second theory proposes that an abnormal x-protein causes the formation of intracellular neurofibrillary tangles. x-Proteins are important in the maintenance of cytoskeleton function and axonal transport of proteins. Another theory is that Ap accumulation is a precipitating factor that is followed by the development of the x-enriched tangles in the dying neurons. 

In order to absolutely confirm the presence of AD, the brain must be biopsied immediately after death. What is found is a general deterioration of brain neurons and the presence of excessive quantities of neurofibrillary tangles (twisted neuron bundles) and amorphous amyloid protein. In 1907 it was the neurofibrillary tangles which Alois Alzheimer first associated with the condition which bears his name. Today clinical psychiatric evaluations, PET brain scans for utilization of glucose as well as NMR are used to help in the diagnosis of AD. It is extremely difficult to differentiate AD from other types of... 

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. 

Numerous in vitro studies have implicated ROS in neuronal death [Leonardi and Mytilineou, 1998], and different markers of oxidative stress are found in postmortem examination of brain tissues from patients with neurodegenerative disorders [Sayre et al., 2001], DNA oxidation, protein oxidation, and lipid peroxidation have been reported in brain regions containing neurofibrillary tangles and senile plaques from Alzheimer s disease (AD) patients [Lovell and Markesbery, 2007 Polidori et al., 2007], Dopaminergic neurons in the substantia nigra of brains of Parkinson s disease (PD) patients also exhibit hallmarks of oxidative stress [Giasson et al., 2002]. 

Magaki et al. [2007] measured the levels of loosely bound, nonheme, and total iron and copper in the frontal cortex and hippocampus of patients with mild-moderate AD (n = 3), severe AD (n = 8), and dementia with Lewy bodies (DLB, n = 6). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD, that is, 5 amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies. A significant decrease of loosely bound iron was found in the hippocampal white matter of both mild-moderate and severe AD patients and a trend toward increased... 

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