Beta-secretase belongs to the protease family. It is involved in the formation of beta-amyloid, which plays important roles in information transmission in the brain. At the same time, beta-secretase and beta-amyloid play important roles in the development of Alzheimer’s disease.
What is beta-secretase?
Beta-secretase belongs to the group of proteases that break down proteins at specific sites. It is located in the membrane of the endoplasmic reticulum and the Golgi apparatus. Its active site contains two aspartate residues. This active site is localized in the extra-membrane region. Beta-secretase is also known as aspartate protease. In its active form, it represents a dimer. In addition to beta-secretase, there is also alpha- and gamma-secretase. All three proteases cleave the protein APP (amyloid precursor protein). Beta and gamma secretase produce beta amyloids. The exact function of APP is not yet known. However, amyloids appear to play important roles in information transmission. What is better known, however, is that beta-amyloids play an important role in the development of Alzheimer’s disease. They can be deposited as amyloid plaques in the brain.
Function, effects, and roles
The function of beta-secretase is to break down the protein APP into beta-amyloids. There are two beta-amyloids, referred to as amyloid-beta 40 and amyloid-beta 42. They are formed with the help of two enzymes beta-secretase and gamma-secretase. Beta-amyloids have an antimicrobial effect. At the same time, they are involved in the formation of the myelin sheaths of the nerve fibers. However, the amyloids are also neurotoxic. They form the so-called amyloid plaques in the brain, which can lead to Alzheimer’s disease. However, these toxic plaques only form when the protein APP is first cleaved by beta-secretase. When cleaved by alpha-secretase, water-soluble proteins are formed that do not form plaques. However, a certain amount of beta-amyloid is necessary for the transmission of information to neurons. Scientific research has even shown that beta-amyloids play a central role in the transmission of information in the brain. However, the mechanism of the processes is not yet well understood.
Formation, occurrence, properties, and optimal levels
Beta-secretase is present in every body cell as a transmembrane component in the endoplasmic reticulum and the Golgi apparatus. It constantly generates beta-amyloids in normal metabolism by cleaving APP for antimicrobial defense. Beta-amyloid deposition does not occur there. Most of the protein APP protrudes from the cell. The smaller part is inside the cell. It is a so-called transmembrane molecule. In addition to beta-secretase, alpha-secretase also cleaves the protein APP into smaller non-amyloid molecules, but these are water soluble and are not deposited anywhere. In contrast to beta-amyloids, the proteins formed by alpha-amyloids have neuroprotective properties. They protect the brain from neurotoxic plaques. During cleavage of the protein APP by beta-secretase, a water-soluble fragment is also cleaved first. Then, as a second step, the residual molecule is cleaved by gamma-secretase into a beta-amyloid and the intracellular domain of APP.
Diseases and disorders
The role of beta-secretase in the development of Alzheimer’s disease is well known. When the concentration of beta-amyloids is elevated, they can be deposited as amyloid plaques in the brain. This leads to the death of neurons and thus to atrophy of the brain. The mechanism of development of senile plaques has not yet been fully elucidated. Beta-amyloids have important functions in the organism. In particular, they play a central role in information processing. However, when their concentration becomes too high, they are deposited as plaques between neurons. There are two competing cleavage pathways of the precursor APP. APP is broken down either by alpha-secretase into water-soluble components or by beta- and gamma-secretase into beta-amyloids. Both reactions are in equilibrium with each other. When this balance is shifted in favor of the second degradation pathway, Alzheimer’s disease develops. Several mutations have been discovered as the cause. However, no mutations affecting beta-secretase play a role.Among other things, a genetically altered APP can become an increased risk for Alzheimer’s disease. The protein APP is encoded by a gene on chromosome 21. Thus, a mutation of this gene can lead to Alzheimer’s disease. Down syndrome also has an increased likelihood of developing dementia based on senile plaques. Here, the concentration of the protein APP is increased because chromosome 21 is present three times. Overall, the cause of the disease has not yet been fully elucidated. In addition to genetic factors, inflammatory processes in the brain, infections with prions, diabetes, elevated cholesterol levels, trauma or environmental influences are also being discussed. It has been suggested, for example, that increased aluminum concentrations in food could cause Alzheimer’s disease. Ultimately, however, the prerequisite for the disease is always the formation of senile amyloid plaques from beta-amyloids. Alzheimer’s disease is characterized by progressive dementia. Cognitive performance decreases and daily activities become increasingly difficult to manage. So far, a curative treatment of the disease is not possible. Only the disease process can be slowed down. Currently, efforts are being made to develop so-called beta-secretase inhibitors. These are drugs that inhibit the activity of beta-secretase in order to stop the disease process in Alzheimer’s disease. So far, there are no beta-secretase inhibitors on the market. The corresponding drug development is still in an early phase. Thus, according to general estimates, the launch of a drug against Alzheimer’s is not expected until 2018 at the earliest.
