List of the scientific projects that received grants

Coordinators:

• INSERM U422 : Luc Buée
• Targeon : Hugues Bienaymé
• INSERM U761 : Benoit Déprez

Mission:

1. Identification of lead compounds active in vitro (enzymatic and phenotypic screen) with suitable early ADME parameters.
2. Identification of Optimized lead compounds with good drugability, demonstrated in vivo activity and suitable PK and toxicity parameters.

Objectives and Rationale :

Alzheimer’s disease was first described one hundred years ago. With the increase in life expectancy, its incidence has increased dramatically and current forecasts speak in terms of a doubling of the number of persons affected every 20 years. Alzheimer’s disease is the most frequently encountered form of dementia (about 70% of cases of dementia). The earliest and most frequent manifestations are benign memory disorders relating to recent facts and, in most cases, concerning details of everyday life. There is then a slow evolution of the symptoms which will gradually spread to organizational and programming disorders (executive functions), language difficulties (aphasia), clumsy gestures (apraxia) and defective recognition of objects, places and persons (agnosia). Today, in France, the diagnosis of Alzheimer's disease is made at a late stage and treatment of patients varies considerably. The symptomatic drugs currently available have only a modest (and sometimes disputed) effect on the evolution of the disease. Other resources exist, seeking to stimulate and consolidate the patient’s functions, to improve his well-being and ability to fend for himself, and to provide support for his family. The definitive diagnosis of Alzheimer’s disease is based on the observation of characteristic brain lesions (usually found during a post-mortem examination): senile plaques and neurofibrillary tangles. Each of these lesions is located in specific areas of the brain. The neurofibrillary pathology is due to the pathological accumulation in the neuron of a naturally present protein, the tau protein. This protein plays a role in the polymerization of the microtubules, while the amyloid pathology is characterized by the extracellular accumulation of a peptide which is normally present in low concentrations: amyloid-beta peptide. As indicated, neurofibrillary degeneration results from the intraneuronal aggregation of tau proteins into paired helical filaments. The presence of these neuropathological lesions is very well correlated with cognitive deficits. Tau proteins are microtubule-associated proteins. They are mostly expressed in neurons. There are six Tau isoforms in the adult human brain generated by alternative splicing from a single gene located on chromosome 17. These proteins play a role in the polymerization and stability of the microtubules. This function is regulated by the state of phosphorylation of Tau proteins. The abnormal phosphorylation of tau proteins results in a disruption of microtubule stability and a loss of axonal transport. Molecules stabilizing the microtubules (taxol derivatives) have therefore been proposed in the treatment of tauopathies. Their use in a clinical situation is, however, highly unlikely. Moreover, certain tauopathies present an overexpression of tau 4R proteins facilitating the stability of the microtubules, and taxol will probably show the same adverse effects. The abnormal phosphorylation of the tau proteins would appear to favor their aggregation in filaments. The use of kinase inhibitors thus holds out promise, with lithium or GSK3b inhibitors being used to slow down the progress of neurofibrillary degeneration. This approach is currently being tested in therapeutic trials.