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 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.
Health Conditions Related to Genetic Changes
Many variants (also called mutations) in the APP gene can cause early-onset Alzheimer disease, which begins before age 65. These variants are responsible for less than 10 percent of all early-onset cases of the disorder.
The most common APP gene variant changes one of the protein building blocks (amino acids) in the amyloid precursor protein. This variant replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). Variants 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.More About This Health Condition
Hereditary cerebral amyloid angiopathy
Variants 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 variants change single amino acids in the amyloid precursor protein. Each of these variants 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 variants 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 that accumulate in the blood vessels of the brain. The amyloid deposits 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 or be life-threatening. Amyloid deposits in specific parts of the brain can interfere with normal brain function, leading to dementia, seizures, movement problems, and other neurological features in some people with hereditary cerebral amyloid angiopathy.More About This Health Condition
Other Names for This Gene
- amyloid beta (A4) precursor protein
- amyloid beta-peptide
- amyloid beta-protein precursor
- amyloid precursor protein
- cerebral vascular amyloid peptide
- protease nexin 2
- protease nexin-II
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
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- Kerr ML, Small DH. Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development. J Neurosci Res. 2005 Apr 15;80(2):151-9. doi: 10.1002/jnr.20408. Citation on PubMed
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- Majersik JJ, Skalabrin EJ. Single-gene stroke disorders. Semin Neurol. 2006 Feb;26(1):33-48. doi: 10.1055/s-2006-933307. Citation on PubMed
- Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, Arbustini E, Palladini G, Diegoli M, Genovese E, Ferrari G, Coverlizza S, Merlini G. A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. doi: 10.1002/ana.20571. Citation on PubMed
- Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer's disease. J Clin Psychiatry. 2006 Apr;67(4):652-70. doi: 10.4088/jcp.v67n0418. Citation on PubMed or Free article on PubMed Central
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- Salameh MA, Robinson JL, Navaneetham D, Sinha D, Madden BJ, Walsh PN, Radisky ES. The amyloid precursor protein/protease nexin 2 Kunitz inhibitor domain is a highly specific substrate of mesotrypsin. J Biol Chem. 2010 Jan 15;285(3):1939-49. doi: 10.1074/jbc.M109.057216. Epub 2009 Nov 17. Citation on PubMed or Free article on PubMed Central
- Wolfe MS, Guenette SY. APP at a glance. J Cell Sci. 2007 Sep 15;120(Pt 18):3157-61. doi: 10.1242/jcs.03481. No abstract available. Citation on PubMed
- Zhang H, Ma Q, Zhang YW, Xu H. Proteolytic processing of Alzheimer's beta-amyloid precursor protein. J Neurochem. 2012 Jan;120 Suppl 1(Suppl 1):9-21. doi: 10.1111/j.1471-4159.2011.07519.x. Epub 2011 Nov 28. Citation on PubMed or Free article on PubMed Central
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