The amyloid peptide precursor in Alzheimer's disease.

beta A4, an hydrophobic peptide containing from 39 to 43 amino acids, is the major constituent of the amyloid core of characteristic lesions of Alzheimer's disease (AD) known as senile plaques. By cDNA cloning, it was demonstrated that beta A4 is derived from a much larger precursor named the amyloid peptide precursor or APP. The isolation of cDNA clones and the characterization of their nucleotide sequence has shown that several APP proteins containing from 365 to 770 amino acids are produced by alternative splicing of a single primary transcript. The major APP isoforms contain a large extracellular N-terminal domain and a short intracellular C-terminal end. The beta A4 sequence itself is contained for 15 amino acids in the transmembrane domain while 28 amino acids are protruding into the extracellular space. The gene encoding APP is located on human chromosome 21, which is involved in the autosomal dominant inheritance of some early onset of familial AD (FAD). In a few families, mutations of the APP gene have been described. Although they can explain less than 3% of all FAD cases, these mutations clearly demonstrate that APP metabolism is involved in the development of AD. The overexpression of APP in several cultured cells allowed to characterize two catabolic pathways of the protein. A non amyloidogenic pathway precludes formation of beta A4, because APP is cleaved by an alpha-secretase within the beta A4 sequence, leading to the extracellular release of a C-terminal truncated protein. The amyloidogenic pathway produces soluble extracellular beta A4, by cleavage of APP by beta- and gamma-secretases after endocytosis of the transmembrane protein. Although soluble beta A4 is non toxic, it becomes very neurotoxic as soon as it makes fibrils. It is therefore essential to characterize the different factors which favor the organization of beta A4 into fibrils. They have to be considered as risk factors for AD, as well as targets for new therapies. Another therapeutic approach could consist in developing molecules able to inhibit beta A4 production by stimulating the non amyloidogenic pathway of APP.