Scientists studying beta-secretese, gamma-secretase, and tau hope to gain a better understanding of how Alzheimer's progresses … and ultimately how to prevent it.
Amyloid plaques and neurofibrillary tangles are the structural hallmarks of Alzheimer's disease. Although plaques and tangles can be seen only at autopsy, they must be present to make a definitive diagnosis of Alzheimer’s. It remains unclear whether these abnormal brain deposits are the cause of Alzheimer’s or simply a byproduct of some other causative agent, but researchers now have a better understanding of how plaques and tangles are formed in Alzheimer's disease. This improved understanding has spawned new attempts to block the underlying process that may lead to their buildup and lead to Alzheimer’s disease. If plaques and tangles are, in fact, the cause of Alzheimer’s, the success of these new approaches may ultimately provide the foundation for effective prevention strategies and treatments.
Amyloid plaques are a mixture of abnormal proteins and nerve cell fragments that develop in the tissue between nerve cells in areas of the brain involved in memory. Their main component is beta-amyloid, a protein fragment that breaks off from a larger molecule called the amyloid precursor protein (APP). APP is part of the cell membrane that encases every nerve cell. When nerve cells die, this large molecule must be broken down and removed from the brain. Enzymes called secretases split the protein in two, forming the small beta-amyloid fragment.
How does this lead to Alzheimer’s disease? Researchers recently identified substances called beta-secretase and gamma-secretase as enzymes that slice the amyloid precursor protein. Beta-secretase and gamma-secretase cut the protein in a place that causes beta-amyloid to become insoluble (less easily dissolved), leaving it to be deposited in the brain. Investigators suspect that blocking beta-secretase or gamma-secretase activity might prevent production of this undesirable form of beta-amyloid, and experiments are currently under way to test this hypothesis. Still a mystery, however, are what happens to the beta-amyloid segment once it separates from the amyloid precursor protein, and how beta-amyloid might cause Alzheimer’s.
Neurofibrillary tangles are the other structural abnormality associated with Alzheimer’s disease. Composed mostly of a protein called tau, these twisted, hairlike threads are what remain after a neuron’s internal support structure (known as microtubules) collapses. In healthy neurons, microtubules function like train tracks to carry nutrients from one destination to another. Tau normally serves as the supporting "railroad ties.” In Alzheimer’s, however, the protein becomes hopelessly twisted and disrupts the function of the microtubules. This defect interferes with communication within nerve cells and eventually leads to their death.
Researchers are not sure why tau goes awry, but an enzyme called Pin1 may play an important role in keeping tau intact. In test-tube experiments, when Pin1 binds to an altered tau, the protein begins to function properly and microtubule assembly is restored. Furthermore, researchers have found substantially lower-than-normal levels of Pin1 in autopsied brains of people with Alzheimer’s. The significance of these findings remains uncertain, but the presence of an enzyme such as Pin1 may help maintain or restore the proper functioning of tau, thereby preventing the formation of tangles. This possibility raises the hope that therapies aimed at preserving the function of tau might one day prevent Alzheimer’s.
