TOWARDS A PHARMACOLOGICAL APPROACH OF ALZHEIMERS-DISEASE BASED ON THEMOLECULAR-BIOLOGY OF THE AMYLOID PRECURSOR PROTEIN (APP)

After heart disease, cancer and stroke, Alzheimer's disease (AD) is th e fourth major cause of death in the developed countries. Due to demog raphic changes, this situation will further worsen in the future. With the use of molecular biology techniques, important progress has recen tly been made in the understanding of the molecular changes leading to some forms of this disabling illness. The first step was the partial sequencing of the amyloid protein accumulating in the senile plaques a nd vascular deposits characteristic of AD. This allowed the cloning of a cDNA coding for a long amyloid precursor protein (APP). During the last few years, independent reports have described the presence of sev eral reproducible point mutations in specific codons of APP in early o nset familial Alzheimer patients. These mutations are responsible for an abnormal processing of APP, leading to the formation of pathologica l beta/A4 amyloid deposits. beta/A4 has been shown to possess neurotro phic properties in embryonic neurones and to be a potent neurotoxic ag ent in differentiated hippocampal neurones. More recently, modificatio ns of intracellular calcium, activation of kinases, free radical gener ation and anomalies in potassium channels have been described as possi ble mechanisms of beta/A4 toxicity. Some forms of Apo-E lipoprotein ma y be an additional risk factor. Hence, it now seems possible to elabor ate a coherent theory to explain the cascade of events leading to the development of AD. Genetically induced point mutations or environmenta l factors may produce a modification of the APP metabolism and process ing. As a consequence, abnormal deposits of beta/A4 are formed. They m ay exert direct or indirect neurotoxic actions. A degeneration of chol inergic, catecholaminergic and other neurones follows, leading to the well known cognitive and behavioural changes of AD. On the basis of th is theory, research projects and experimental tools aimed at screening drugs potentially active on different steps of the APP pathological c ascade may be proposed. They will be presented in the next pages, taki ng into account the technical possibilities and limitations of our lab oratory, in the fields of cellular and molecular biology as well as el ectrophysiology. 1) The potential protective action of drugs against t he neuronotoxic effect of beta/A4 fragments and other neurotoxins will be studied in hippocampal cell cultures. 2) The effect of beta/A4 on the electrophysiological activity of rat brain neurones and the antago nistic action of the tested drug will be studied in hippocampal slices . Other pathological conditions such as hypoxia, free radical formatio n and lipid peroxidation will also be used. 3) When appropriate, the a ction of the drug on cholinergic neurones of the septum medialis and C A1 hippocampal pyramidal cells will be studied by means of extra- or i ntracellular recording techniques. 4) Potential protective drugs actin g on neuronal potassium channels may also be studied by these electrop hysiological techniques.