APP

The APP gene codes for amyloid-beta precursor protein (APP) [R].

APP can be cut into smaller pieces by enzymes in the body. This process generates amyloid-beta and other proteins. Amyloid-beta has been implicated in the progression of Alzheimer’s disease [R].

Other proteins generated by APP cleavage may be required for brain development, learning and memory, and protection from brain injuries [R]. 

Some mutations in APP have been linked to early-onset (before age 65) Alzheimer’s disease. These mutations increase the amount of amyloid-beta produced [R, R]. 

Other APP mutations may offer protection against Alzheimer’s disease development [R]. 

Notably, people with Down syndrome are at greater risk of Alzheimer’s disease. This is because the APP gene is located on chromosome 21. People with Down syndrome carry an extra copy of this chromosome, which means they produce more APP protein and in turn, more amyloid-beta [R]. 

The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the brain and spinal cord (central nervous system). Little is known about the function of amyloid precursor protein. Researchers speculate that it may bind to other proteins on the surface of cells or help cells attach to one another. Studies suggest that in the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.

Amyloid precursor protein is cut by enzymes to create smaller fragments (peptides), some of which are released outside the cell. Two of these fragments are called soluble amyloid precursor protein (sAPP) and amyloid beta (β) peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells (neurons) in the brain both before and after birth. The sAPP peptide may also control the function of certain other proteins by turning off (inhibiting) their activity. Amyloid β peptide is likely involved in the ability of neurons to change and adapt over time (plasticity). Other functions of sAPP and amyloid β peptide are under investigation.

More than 50 different mutations in the APP gene can cause early-onset Alzheimer disease, which begins before age 65. These mutations are responsible for less than 10 percent of all early-onset cases of the disorder. The most common APP mutation changes one of the protein building blocks (amino acids) in the amyloid precursor protein. This mutation replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). Mutations in the APP gene can lead to an increased amount of the amyloid β peptide or to the production of a slightly longer and stickier form of the peptide. When these protein fragments are released from the cell, they can accumulate in the brain and form clumps called amyloid plaques. These plaques are characteristic of Alzheimer disease. A buildup of toxic amyloid β peptide and amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of this disorder. hereditary cerebral amyloid angiopathy At least six mutations in the APP gene have been found to cause hereditary cerebral amyloid angiopathy, a condition characterized by stroke and a decline in intellectual function (dementia), which begins in mid-adulthood. These mutations change single amino acids in the amyloid precursor protein. All of the APP gene mutations that cause hereditary cerebral amyloid angiopathy lead to changes near the beginning of the protein sequence. Each of these mutations causes a different type of the condition. The Dutch type, the most common of all the types, is caused by the replacement of the amino acid glutamic acid with the amino acid glutamine at position 22 in the protein sequence (written as Glu22Gln or E22Q). The Italian type and Arctic type are also caused by changes to glutamic acid at position 22. In the Italian type, glutamic acid is replaced with the amino acid lysine (written as Glu22Lys or E22K) and in the Arctic type, glutamic acid is replaced with the amino acid glycine (written as Glu22Gly or E22G). The Flemish type is caused by replacement of the amino acid alanine with glycine at position 21 (written as Ala21Gly or A21G). In the Iowa type, the amino acid aspartic acid is switched with the amino acid asparagine at position 23 (written as Asp23Asn or D23N). The Piedmont type of hereditary cerebral amyloid angiopathy is caused by the replacement of the amino acid leucine at position 34 with the amino acid valine (written as Leu34Val or L34V). The result of all of these mutations is the production of an amyloid β peptide that is more prone to cluster together (aggregate) than the normal peptide. The aggregated protein forms amyloid deposits known as plaques that accumulate in the blood vessels of the brain. The amyloid plaques replace the muscle fibers and elastic fibers that give blood vessels flexibility, causing the blood vessels to become weak and prone to breakage. In the brain, such a break causes bleeding (hemorrhagic stroke), which can lead to brain damage and dementia. Amyloid plaques in specific parts of the brain can interfere with brain function, leading to seizures, movement problems, and other neurological features in some people with hereditary cerebral amyloid angiopathy.

The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the brain and spinal cord (central nervous system). Little is known about the function of amyloid precursor protein. Researchers speculate that it may bind to other proteins on the surface of cells or help cells attach to one another. Studies suggest that in the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development. Amyloid precursor protein is cut by enzymes to create smaller fragments (peptides), some of which are released outside the cell. Two of these fragments are called soluble amyloid precursor protein (sAPP) and amyloid beta (β) peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells (neurons) in the brain both before and after birth. The sAPP peptide may also control the function of certain other proteins by turning off (inhibiting) their activity. Amyloid β peptide is likely involved in the ability of neurons to change and adapt over time (plasticity). Other functions of sAPP and amyloid β peptide are under investigation.