THE CARBOXYL-TERMINAL 100 AMINO-ACIDS OF THE BETA-AMYLOID PROTEIN-PRECURSOR - ROLE IN ALZHEIMER-DISEASE NEURODEGENERATION

The relationship between two crucial processes in Alzheimer disease, the formation of insoluble deposits of amyloid in plaques and in blood vessels, and the degeneration of neurons, is incompletely understood. The principal component of amyloid deposits is a protein fragment termed A beta (also called A4). Following the cloning, by our laboratory and others, of the gene encoding the normal precursor protein for A beta, we used genetic intervention technology to show that a 100 amino acid fragment of the amyloid protein precursor (beta APP) that contains A beta (called beta APP-C100) is toxic specifically to nerve cells. Transgenic mice expressing beta APP-C100 in the brain under control of the dystrophin brain promoter were generated, and shown to accumulate deposits of A beta in the brain, both intracellularly and around blood vessels. Lysosomal inclusions and accumulations of beta APP epitopes in the lysosomes were revealed in the CNS of these mice. In parallel work, we discovered that beta APP-C100 binds to a specific receptor on the surface of many neurons in order to destroy these cells. We describe the receptor pharmacologically, and we discuss the intraneuronal signal transduction pathways that may be activated when beta APP-C100 binds to the receptor. The knowledge gained from these studies may be useful for developing therapeutic agents that can halt or reverse the processes of amyloid deposition and neurodegeneration that occur in Alzheimer disease.