Amyloid precursor protein (APP), the starting point for amyloid plaques, is one of many proteins associated with the cell membrane, the barrier that encloses the cell. As it is being made inside the cell, APP becomes embedded in the membrane, like a toothpick stuck through the skin of an orange (Figure 1). In a number of cell compartments, including the outermost cell membrane, specific enzymes snip, or cleave, APP into discrete fragments. In 1999 and 2000, scientists identified the enzymes responsible for cleaving APP. These enzymes are called alpha-secretase, beta-secretase, and gamma-secretase. In a major breakthrough, scientists then discovered that, depending on which enzyme is involved and the segment of APP where the cleaving occurs, APP processing can follow one of two pathways that have very different consequences for the cell. In the benign pathway, alpha-secretase cleaves the APP molecule within the portion that has the potential to become beta-amyloid. This eliminates the production of the beta-amyloid peptide and the potential for plaque buildup. The cleavage releases from the neuron a fragment called sAPPα, which has beneficial properties, such as promoting neuronal growth and survival. The remaining APP fragment, still tethered in the neuron’s membrane, is then cleaved by gamma-secretase at the end of the beta-amyloid segment. The smaller of the resulting fragments also is released into the space outside the neuron, while the larger fragment remains within the neuron and interacts with factors in the nucleus (Figure 2). In the harmful pathway, beta-secretase first cleaves the APP molecule at one end of the beta-amyloid peptide, releasing sAPPβ from the cell (Figure 3). Gamma-secretase then cuts the resulting APP fragment, still tethered in the neuron’s membrane, at the other end of the beta-amyloid peptide. Following the cleavages at each end, the beta-amyloid peptide is released into the space outside the neuron and begins to stick to other beta-amyloid peptides (Figure 4). These small, soluble aggregates of two, three, four, or even up to a dozen beta-amyloid peptides are called oligomers. Specific sizes of oligomers may be responsible for reacting with receptors on neighboring cells and synapses, affecting their ability to function. It is likely that some oligomers are cleared from the brain. Those that cannot be cleared clump together with more beta-amyloid peptides. As the process continues, oligomers grow larger, becoming entities called protofibrils and fibrils. Eventually, other proteins and cellular material are added, and these increasingly insoluble entities combine to become the well-known plaques that are characteristic of AD. For many years, scientists thought that plaques might cause all of the damage to neurons that is seen in AD. However, that concept has evolved greatly in the past few years. Many scientists now think that oligomers may be a major culprit. Many scientists also think that plaques actually may be a late-stage attempt by the brain to get this harmful beta-amyloid away from neurons. |
