Amyloid precursor protein



Amyloid precursor protein (APP) is an is_associated_with::integral membrane protein expressed in many tissues and concentrated in the is_associated_with::synapses of is_associated_with::neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, is_associated_with::neural plasticity and iron export. APP is best known as the precursor molecule whose is_associated_with::proteolysis generates is_associated_with::beta amyloid (Aβ), a 37 to 49 is_associated_with::amino acid is_associated_with::peptide whose is_associated_with::amyloid fibrillar form is the primary component of is_associated_with::amyloid plaques found in the brains of is_associated_with::Alzheimer's disease patients.

Genetics
APP is an ancient and highly conserved protein. In is_associated_with::humans, the is_associated_with::gene for APP is located on is_associated_with::chromosome 21 and contains 18 is_associated_with::exons spaning 290 is_associated_with::kilobases. Several is_associated_with::alternative 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 proteins have been identified in other organisms such as is_associated_with::Drosophila (fruit flies), C. elegans (roundworms), and all is_associated_with::mammals. 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 biological functions.

Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta (Aβ), 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.

A mutation (A673T) in the APP gene protects against Alzheimer’s disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro.

Structure
A number of distinct, largely independently-folding structural domains 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 is_associated_with::growth factor-like domain (GFLD) and a is_associated_with::copper-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 is_associated_with::growth factor-like domain, the is_associated_with::copper-binding domain, the complete E1 domain and the E2 domain.

Post-translational processing
APP undergoes extensive is_associated_with::post-translational modification including is_associated_with::glycosylation, is_associated_with::phosphorylation, is_associated_with::sialylation, and is_associated_with::tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments. It is commonly cleaved by is_associated_with::proteases in the is_associated_with::secretase family; is_associated_with::alpha secretase and is_associated_with::beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with is_associated_with::apoptosis. Cleavage by is_associated_with::gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include is_associated_with::presenilin, 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 is_associated_with::lipid rafts. 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 is_associated_with::cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and is_associated_with::apolipoprotein E is_associated_with::genotype 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 expression is upregulated during neuronal differentiation and after neural injury. Roles in is_associated_with::cell signaling, is_associated_with::long-term potentiation, and is_associated_with::cell adhesion 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.

APP is_associated_with::knockout mice are viable and have relatively minor phenotypic 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.

Anterograde neuronal transport
Molecules synthesized in the cell bodies of neurons must be conveyed to the outward to distal synapses. This is accomplished via fast anterograde transport. It has been found that APP can mediate interaction between cargo and is_associated_with::kinesin and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein.

Additionally, it has been shown that the interaction between APP and kinesin is specific to the peptide sequence of APP. In a recent experiment involving transport of peptide-conjugated colored beads, controls were conjugated to a single amino acid, is_associated_with::glycine, such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that the terminal COOH moiety of peptides is not sufficient to mediate transport.

Iron export
A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses is_associated_with::ferroxidase activity similar to is_associated_with::ceruloplasmin, facilitating iron export through interaction with is_associated_with::ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's. It has been shown that a is_associated_with::single nucleotide polymorphism in the is_associated_with::5'UTR of APP is_associated_with::mRNA can disrupt its translation.

The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity.

As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize the iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin).

Hormonal regulation
The amyloid-β precursor protein (AβPP) and all associated secretases are expressed early in development and plays a key role in the is_associated_with::endocrinology of reproduction – with the differential processing of AβPP by secretases regulating is_associated_with::human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone is_associated_with::human chorionic gonadotropin (hCG) increases AβPP expression and hESC proliferation while is_associated_with::progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC.

AβPP and its cleavage 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 is_associated_with::cell cycle. It is postulated that the loss of sex steroids (including progesterone) but the elevation in is_associated_with::luteinizing hormone, the adult equivalent of hCG, post-is_associated_with::menopause and during is_associated_with::andropause drives amyloid-β production 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 bind together to form coil like structures that are not resorbed. Also, it induces secondary inflammation, which may cause local damage.

Interactions
Amyloid precursor protein has been shown to interact with:


 * is_associated_with::APBA1,
 * is_associated_with::APBA2,
 * is_associated_with::APBA3,
 * is_associated_with::APBB1,
 * is_associated_with::APPBP1,
 * is_associated_with::APPBP2,
 * is_associated_with::BCAP31,
 * is_associated_with::BLMH
 * is_associated_with::CLSTN1,
 * CAV1,
 * COL25A1,
 * is_associated_with::FBLN1,
 * GSN,
 * is_associated_with::HSD17B10, and
 * is_associated_with::SHC1.

APP interacts with is_associated_with::reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.