Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by the progressive and irreversible loss of associative cortical neurons. The degenerating process and the resulting neuronal loss lead first to memory impairment and later to dementia. At the end of the disease, most, if not all the cortical brain areas, as well as many subcortical nuclei, are heavily filled with two different types of lesions: senile plaques and neurofibrillary tangles. Senile plaques are spherical extracellular amyloid deposits while neurofibrillary tangles correspond to an intra-neuronal accumulation of pathological fibrils called Paired Helical Filaments or PHF.

The discovery of molecular components of Alzheimer lesions has given invaluable information about the etiology of the disease and the nature of the biochemical dysfunctions that lead to neuronal-cell death. Here, we present the information unravelled by studying pathological Tau proteins which are the basic components of PHF. These proteins, as reliable markers of the degenerating process, help us to understand many aspects of the disease and several features of other neurodegenerative disorders as well as normal aging. Finally, we will show that pathological Tau proteins could be used for setting up a biological diagnostic test of AD and an experimental model of the Alzheimer-type neurodegeneration.

In 1985, Jean-Pierre Brion and coworkers demonstrated that antibodies against tau proteins strongly labeled neurofibrillary tangles. Then, many teams, including ours, demonstrated that tau proteins are the main components of paired helical filaments (PHF), that PHF-tau are hyperphosphorylated, that antibodies against phosphorylated sites on tau strongly immunodetect PHF and neurofibrillary degeneration: this is the case for AD2, a monoclonal antibody developed in collaboration with Sanofi Diagnostic Pasteur (figure above). AD2 detects tangles, degenerating neurites and neuritic plaques, as well as tau pathology and tauopathies.