Beta-amyloid: From APP to Plaques (But Not Always)
It’s a tale with terrific characters: elusive enzymes, a principal player protein whose ultimate character (hero or villain) depends on the location of a cut, and plaques that maybe aren’t the evildoers everyone thought they were. After painstaking research, many scientists in laboratories across the country have teased apart the biological clues provided by these characters. The result? A storyline that continues to evolve, some radically new thinking about beta-amyloid and plaques, and several potentially promising new treatment approaches.
The story starts with amyloid precursor protein (APP), a large protein that is thought to be important to the health of neurons. APP is embedded in the neuronal membrane, residing partly inside and outside the cell. At some point, APP is cut, or cleaved, into several fragments. For a long time, scientists were pretty certain that one or more enzymes (proteins that cause or speed up a chemical reaction) were responsible for this cleaving, but they weren’t able to identify them. Eventually, investigators identified the three cleaving enzymes, which they named alpha-secretase, beta-secretase, and gamma-secretase. In a major breakthrough, scientists discovered that, depending on which enzyme does the cleaving and where the cleaving happens, APP processing can follow one of two pathways that have very different consequences.
In one, considered the usual pathway, alpha-secretase cleaves the APP molecule within the portion that has the potential to become beta-amyloid. Cleaving at this site results in the release into the space outside the neuron of a fragment called sAPPa. This fragment may have 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 sequence. The smaller of the resulting fragments also is released, while the larger fragment remains within the neuron and is believed to enter the nucleus. No beta-amyloid is produced in this pathway.
In the second pathway, beta-secretase cleaves the APP molecule at one end of the portion that has the potential to become beta-amyloid, releasing a fragment called sAPPa. Then, gamma-secretase cleaves the remaining fragment at the other end of the beta-amyloid sequence. Following its cleavage at both ends, a beta-amyloid peptide is released into the space outside the neuron. This pathway spells trouble for neurons because the beta-amyloid peptide begins to stick together with other similarly cleaved beta-amyloid peptides. These small, soluble beta-amyloid clumps are called Aß-derived diffusible ligands, or ADDLs. The number of individual beta-amyloid peptides within ADDLs varies, but collectively, they are called “oligomers.” It is likely that some oligomers are cleared from the brain. If they cannot be cleared from the brain, they clump together with more beta-amyloid peptides and other proteins and cellular material. As the process continues, these clumps grow larger, becoming increasingly insoluble entities called protofibrils and fibrils. Eventually they coalesce into the well-known plaques that are characteristic of AD. The rate at which beta-amyloid aggregates to form plaques is likely to be slowed by lowering the rate at which it is made or by increasing the rate at which it is degraded or physically removed from the brain.
Being able to spell out with greater clarity the sequence of steps from APP to beta-amyloid peptides to plaques has allowed scientists to think in new ways about these AD players. Many scientists now think that oligomers may be the most toxic culprit, not plaques. This thinking also has allowed investigators to pursue avenues of related research that may ultimately lead to new AD treatments.
 |
