Amyloid precursor protein
Encyclopedia
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...
expressed in many tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
and concentrated in the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export. APP is best known and most commonly studied as the precursor molecule whose proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
generates beta amyloid (Aβ), a 39- to 42-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
whose amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
patients.
Genetics
In humanHuman
Humans are the only living species in the Homo genus...
s, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for APP is located on chromosome 21 and contains at least 18 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s in 240 kilobases. Several alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease. Homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
proteins have been identified in other organisms such as Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
(fruit flies), C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
(roundworms), and all mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s. The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state
Native state
In biochemistry, the native state of a protein is its operative or functional form. While all protein molecules begin as simple unbranched chains of amino acids, once completed they assume highly specific three-dimensional shapes; that ultimate shape, known as tertiary structure, is the folded...
biological functions.
Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease. For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.
Structure
A number of distinct, largely independently-foldingProtein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
structural domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
have been identified in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain
Growth factor-like domain
A growth factor-like domain is a protein domain structurally related to epidermal growth factor, which has a high binding affinity for the epidermal growth factor receptor. As structural domains within larger proteins, GFLD regions commonly bind calcium ions...
(GFLD) and a copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
-binding domain (CuBD) interacting tightly together. A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain
Growth factor-like domain
A growth factor-like domain is a protein domain structurally related to epidermal growth factor, which has a high binding affinity for the epidermal growth factor receptor. As structural domains within larger proteins, GFLD regions commonly bind calcium ions...
, the copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
-binding domain, the complete E1 domain and the E2 domain.
Post-translational processing
APP undergoes extensive post-translational modification including glycosylationGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, and tyrosine sulfation
Tyrosine sulfation
Tyrosine sulfation is a posttranslational modification where a sulfate group is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi apparatus may be sulfated...
, as well as many types of proteolytic
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
processing to generate peptide fragments. It is commonly cleaved by protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s in the secretase
Secretase
Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.thumb|300px|right|Processing of the amyloid precursor protein Among other roles in the cell, secretases act on the amyloid precursor protein to cleave the protein into three fragments...
family; alpha secretase
Alpha secretase
Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta...
and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Cleavage by gamma secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
within the membrane-spanning domain generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...
, whose gene has been identified as a major genetic risk factor for Alzheimer's.
The amyloidogenic processing of APP has been linked to its presence in lipid raft
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
s. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. Gamma secretase activity has also been associated with lipid rafts. The role of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
are major risk factors for Alzheimer's disease.
Biological function
Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive.Synaptic formation and repair
The most-substantiated role for APP is in synaptic formation and repair; its expressionGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
, long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
, and cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
have been proposed and supported by as-yet limited research. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
. APP knockout mice are viable and have relatively minor phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
effects including impaired long-term potentiation and memory loss without general neuron loss. On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation. The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia.
Iron export
A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasminCeruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
, facilitating iron export through interaction with ferroportin
Ferroportin
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:*Enterocytes in the duodenum*Hepatocytes...
; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's.
Hormonal regulation of AβPP expression and processing during embryogenesis and Alzheimer’s disease
The amyloid-β precursor protein (AβPP) and all associated secretases are expressed early in development and plays a key role in the endocrinology of reproductionEndocrinology of reproduction
Hormonal regulation occurs at every stage of development. A milieu of hormones simultaneously affects development of the fetus during embryogenesis and the mother, perhaps most notably human chorionic gonadotropin and progesterone .- Embryogenesis :...
– with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
as well as their differentiation
Differentiation
Differentiation may refer to:* Differentiation , the process of finding a derivative* Differentiated instruction in education* Cellular differentiation in biology* Planetary differentiation in planetary science...
into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hCG) increases AβPP expression and hESC proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
while progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
directs AβPP processing towards the non-amyloidogenic pathway which promotes hESC differentiation into NPC
APP and its cleavage
Cleavage
Cleavage may refer to:*Cleavage , partial exposure of the separation between a woman's breasts.**Cleavage enhancement, methods of making a person's breast cleavage look more substantial than it really is....
products do not promote the proliferation and differentiation of post-mitotic neurons; rather the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
(McPhie et al., 2003, J. Neurosci.). It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
, the adult equivalent of hCG, post-menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
and during andropause
Andropause
Andropause or male menopause, sometimes colloquially called "man-opause" is a name that has been given to a menopause-like condition in aging men...
drives amyloid-β production (Bowen et al., 2004) and re-entry of post-mitotic neurons into the cell cycle.
Arthritis
Recently amyloid precursor protein (APP) origin was demonstrated with arthritogenic animals. The source noted is breakdown of immune complexes, where the amyloid aggregates are left degraded and binds together to form coil like structure that is not resorbed. Finally it induces secondary inflammation which may cause local damage.Interactions
Amyloid precursor protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with APBA3
APBA3
Amyloid beta A4 precursor protein-binding family A member 3 is a protein that in humans is encoded by the APBA3 gene.-Interactions:APBA3 has been shown to interact with Amyloid precursor protein.-Further reading:...
, CLSTN1
CLSTN1
Calsyntenin-1 is a protein that in humans is encoded by the CLSTN1 gene.-Interactions:CLSTN1 has been shown to interact with APBA2 and Amyloid precursor protein.-Further reading:...
, APPBP1
APPBP1
NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.-Interactions:APPBP1 has been shown to interact with UBE1C, TRIP12 and Amyloid precursor protein.-Further reading:...
, Gelsolin
Gelsolin
Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency...
, BCAP31
BCAP31
B-cell receptor-associated protein 31 is a protein that in humans is encoded by the BCAP31 gene.-Interactions:BCAP31 has been shown to interact with Caspase 8, VAMP3, BCL2-like 1, Bcl-2 and Amyloid precursor protein.-Further reading:...
, Caveolin 1, FBLN1
FBLN1
FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein.- Function :Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin-containing fibers and basement membranes...
, Collagen, type XXV, alpha 1, APBB1
APBB1
Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.-Interactions:APBB1 has been shown to interact with APLP2, TFCP2, LRP1 and Amyloid precursor protein.-Further reading:...
, APBA2
APBA2
Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.-Interactions:APBA2 has been shown to interact with CLSTN1, RELA and Amyloid precursor protein.-Further reading:...
, APBA1
APBA1
Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.-Interactions:APBA1 has been shown to interact with KCNJ12, CCS, CASK and Amyloid precursor protein.-Further reading:...
, APPBP2
APPBP2
Amyloid protein-binding protein 2 is a protein that in humans is encoded by the APPBP2 gene.-Interactions:APPBP2 has been shown to interact with Amyloid precursor protein.-Further reading:...
, HSD17B10
HSD17B10
3-hydroxyacyl-CoA dehydrogenase type-2 is an enzyme that in humans is encoded by the HSD17B10 gene...
, BLMH
BLMH
Bleomycin hydrolase is an enzyme that in humans is encoded by the BLMH gene.-Interactions:BLMH has been shown to interact with RPL29, RPL11, UBE2I and Amyloid precursor protein.-Further reading:...
and SHC1
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
.
One group of scientists reports that APP interacts with reelin
Reelin
Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the...
, a protein implicated in a number of brain disorders, including Alzheimer's disease.