Amyloid precursor protein (APP) has many functions and regulations. This protein is involved in neural development. Many may know it for its involvement in the pathology of Alzheimer disease as well as other neurodegenerative diseases. However, APP is a developmental gene. This gene contains many functions such as regulating neurons, their differentiation and the regulation of migration. This gene is also associated in neurite outgrowth and the regulation of neural development (1). Despite knowledge of these functions, many functions of APP is still unclear (2).
APP gene is located on the 21st chromosome and is found throughout the body (5). It is composed of many domains; an extracellular N-terminal and a small cytoplasmic domain (3). Several enzymes cut the protein to create small fragments. These fragments are soluble amyloid precursor proteins (sAPP) and amyloid ? (A?). Both of these fragments are known to play important roles in the function of APP. sAPP is involved in growth-promoting properties and inhibits the activity of other proteins. It is also known to be involved in the formation of nerve cells. The A? peptide is known to be involved in the plasticity of neurons (4). However, the A? peptide is 39-43 amino acids long and when is not properly formed due to mutations, it causes neurodegenerative diseases such as Alzheimer disease (3).
APP contains many functions. The main function of APP is that it is involved in neural development. This is shown by APP having a role in neuronal migration and embryogenesis (6). Neuronal migration is regulated by the interactions of the cytoskeleton and other nearby proteins (6). Another function of APP is that it consists of the aid in movement of nerve cells in the brain (4). APP is also involved in neural differentiation. This is due to the over expression of APP in human stem cells (1). Additionally, APP has been shown to activate neurite outgrowth (2). These functions of APP are shown to be involved in neural development. Therefore, APP is a complex protein that posses many functions, many of which are still not very well understood.
Fig 1: Roles of APP and its metabolites during neural development
As mentioned earlier APP is found to be involved in neural development. The functions discussed above have shown how. During early development, the expression pattern of APP in neuroblasts and neurons in the neural tube suggests a role in neurogenesis, including neural proliferation, differentiation and axonal outgrowth (9). Figure 1 shows neural development from early stages. It shows how APP and APP metabolites play important roles during the different stages of neural development. The stages range from neural proliferation to the formation of a functional synapse. The metabolites that posses an upward arrow represent a positive effect, whereas the metabolites with unknown effects are indicated with a question mark (1). There is still much to learn how APP is involved in neural development. Many studies and experiments are currently being done to study the functions of this protein.
There are many factors that regulate APP. Some of these are neurotransmitters, hormones and various protein kinases. These factors have an effect on the proteins fragments which in turn has an effect on the protein. One neurotransmitter that regulates APP is HEK 293. This neurotransmitter over expresses the acetylcholine receptor, which increases the release of sAPP. Glutamate also increased the release of sAPP, and therefore aided in the regulation of APP (7). Protein kinase C (PKC) also regulates the secretion APP. PKC regulates the cleavage of APP. Additionally, PKC increases the release of sAPP and decreases the release of A?. However, PKA inhibits the release of sAPP (7). Various protein kinases are shown to regulate APP. Cholesterol,
a steroid hormone, also regulates APP. An increase of cholesterol inhibits the release of sAPP. However, a decrease in cholesterol decreased the release of A? (7). This is how cholesterol regulates APP. Therefore amyloid precursor protein is regulated by these various factors.
APP is involved in the pathology of some neurodegenerative diseases such as Alzheimer disease. APP and its cleavage product, A?, have been extensively studied in relation to Alzheimer disease (8). It is believed that the A? peptide can induce neurotoxic responses in the brain which may lead to Alzheimer disease (10). Additionally amyloid plaques are formed and accumulate preferably in the cerebral cortex. There are two types, dense and diffuse (11). The amyloid cascade hypothesis suggests that A? accumulation in the brain is the primary event during Alzheimer disease pathology. This hypothesis explains that the imbalance between A? productions and clearance is the main cause of this disease. This imbalance gradually increases the A?42 levels in the brain, resulting in oligomerization which initiates synaptic dysfunction and neuronal loss. Futhermore, increased deposition of A? may trigger alterations and formation of neurofibrillary tangles (11).
The pathological characteristics of Alzheimer disease are known to be amyloid plaques and neurofibrillary tangles which are composed of A? and hyperphosphorylated tau. In addition, large amounts of neuritic degeneration have been noticed including a loss of cholinergic fibers. As mentioned, the A? peptide is believed to play an important role in Alzheimer disease pathogenesis, however this is due to the mutations in the gene that are associated in terms of early-onset Alzheimer disease. These mutations can either cause a high production of A? or it can increase the more fibrillogenic A? (11).
Therefore, APP is a complex and interesting protein that contains many regulations and functions. However, it is also involved in the pathology of one of the most common neurodegenerative disease; Alzheimer disease. Despite that most of the functions of APP is still unknown, there are a lot of functions that are known. Due to this knowledge of how APP is regulated we can learn its involvement in Alzheimer disease. One of its most important functions is that APP is involved in neural development. Knowing this helps us understand the pathology of neurodegenerative diseases.