Key factors in Alzheimer's disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport

During the last years it has become evident that the beta -amyloid (A beta) component of senile plaques may be the key molecule in the pathology of Al zheimer's disease (AD). The source and place of the neurotoxic action of A beta, however, is still a matter of controversy. The precursor of the beta -amyloid peptide is the predominantly neuronal beta -amyloid precursor prot ein. We, and others, hypothesize that intraneuronal misregulation of APP le ads to an accumulation of A beta peptides in intracellular compartments. Th is accumulation impairs APP trafficking, which starts a cascade of patholog ical changes and causes the pyramidal neurons to degenerate. Enhanced A bet a secretion as a function of stressed neurons and remnants of degenerated n eurons provide seeds for extracellular A beta aggregates, which induce seco ndary degenerative events involving neighboring cells such as neurons, astr oglia and macrophages/microglia.