The biochemical parameters of tau pathology 

Introduction

Tau proteins are the basic components of the pathological filaments that accumulate in neurons and glial cells affected by neurofibrillary degeneration (Iqbal et al. 1998, Buée et al. 2000). Tau pathology is observed in more than 20 different diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), myotonic dystrophy (MyoD), familial frontotemporal dementia with Parkinsonism associated to chromosome 17 (FTDP-17), etc. Tau is an outstanding marker well correlated with clinical manifestations. Indeed, pathological tau proteins observed in the association neocortical areas are systematically associated with dementia. Also, tau pathology in the association brain areas is a degenerating process specific to humans. Together, tau pathology reveals precisely the intensity and the extent of the degenerating process (Delacourte and Buée 2000). This pathological entity can be defined according to 6 different molecular parameters that are presented here.

• Neurofibrillary degeneration (NFD)
1. A modern definition

Neurofibrillary degeneration (NFD) is a degenerating process visualized at the histological level by silver stains, as demonstrated by Aloïs Alzheimer and colleagues at the beginning of the 20^th century (Alzheimer 1907). This technique is still used for neuropathological examination, and reveals in detail the abnormal intracellular fibrils that accumulate in cell bodies and in neurites: neurofibrillary tangles, neuropile threads and dystrophic neurites of senile plaques. These lesions are composed of bundles of filaments that result from the aggregation of tau proteins. Using antibodies against tau, it has been shown that NFD is a degenerating process found in numerous neurodegenerative disorders. All approaches combined, the modern definition of neurofibrillary degeneration is the following: a degenerating process characterized by the abnormal filamentous accumulation of tau proteins in neurons and glial cell.

 

• Pathologies with neurofibrillary degeneration

NFD is observed in more that 20 other neurodegenerative disorders (table I). All these diseases are very different, in that they are familial or sporadic, with different origins, from mutations on tau gene to traumatisms. NFD is a many-sided pathological process that can affect preferentially either subcortical nuclei or neocortical areas, neurons or in addition astrocytes or oligodendrocytes. The pattern of NFD lesions is also different and characteristic, according to the type of cell affected, and the subcellular location, such as the Pick bodies of Pick's disease (PiD) or the neuritic plaques of Alzheimer's disease. At the electron microscopic level, the filamentous material of NFD is either helical 5AD), twisted (PSP, CBD) or mainly straight (PiD) (Delacourte and Buée 2000).

• The role of tau proteins

Tau proteins belong to the microtubule-associated proteins (MAP) family. The human tau gene is unique and located over 100 kb on the long arm of chromosome 17 at band position 17q21, and contains 16 exons. Exons 2, 3 and 10 are alternatively spliced and are adult brain-specific. In the human brain, the tau primary transcript gives rise to six mRNAs, three of them with exon 10. Translation of exon 10 adds a fourth repeated sequence which is a binding site to tubulin dimers, the basic components of microtubules. The normal role of tau is to stabilize microtubules, which are the tracks of the intraneuronal transport. Stabilization of microtubules is dramatically increased by tau isoforms with 4 repeated binding sites (4R tau or tau E10+ isoforms). Conversely, phosphorylation of tau destabilizes microtubules and it is suggested that abnormal phosphorylation, as observed in AD, provokes a collapse of the microtubule network and neurodegeneration (Buée et al. 2000).

Buée L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev, 33, 95-130.

Delacourte A, Buée L (2000) Tau pathology: a marker of neurodegenerative disorders. Current Opinion in Neurology, 13, 371-376.

Iqbal K, Alonso AC, Gong CX, Khatoon S, Pei JJ, Wang JZ, et al. (1998) Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles. J Neural Transm Suppl, 53, 169-80.