Cellular and molecular basis of β-amyloid precursor protein metabolism

In molecular neurobiology, perhaps no molecule has been as thoroughly examined as Alzheimer's beta-amyloid precursor protein (beta APP). In the years since the cDNA encoding beta APP was cloned, the protein has been the subject of unparalleled scrutiny on all levels. From molecular genetics and cellular biology to neuroanatomy and epidemiology, no scientific discipline has been left unexplored - and with good reason. beta-amyloid (A beta) is the main constituent of the amyloidogenic plaques which are a primary pathological hallmark of Alzheimer's disease, and beta APP is the protein from which A beta is cleaved and released. Unraveling the molecular events underlying A beta generation has been, and remains, of paramount importance to scientists in our field. In this review we will trace the progress that has been made in understanding the molecular and cellular basis of beta APP trafficking and processing, or alternatively stated, the molecular basis for A beta generation. Imperative to a complete understanding of A beta generation is the delineation of its subcellular localization and the identification of proteins that play either direct or accessory roles in A beta generation. We will focus on the regulation of beta APP cleavage through diverse signal transduction mechanisms and discuss possible points of therapeutic intercession in what has been postulated to be a seminal molecular step in the cascade of events terminating in the onset of dementia, loss of neurons, and eventual death from Alzheimer's disease.