Processing of the amyloid precursor protein
amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Identifiers
Symbol	APP
Alt. Symbols	AD1
Entrez	351
HUGO	620
OMIM	104760
RefSeq	NM_000484
UniProt	P05067
Other data
Locus	Chr. 21 q21.2

Amyloid beta (Aβ or Abeta) is a peptide of 39-43 amino acids that is the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold shared by other peptides such as prions associated with protein misfolding diseases. Image File history File links Download high-resolution version (1199x899, 55 KB) Depiction of amyloid precursor protein processing, created by I. Peltan Ipeltan I, the creator of this work, hereby release it into the public domain. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... Hugo is a masculine name. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Short and long arms Chromosome. ... Chromosome 21 is one of the 23 pairs of chromosomes in humans. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... Phenylalanine is one of the standard amino acids. ... Amyloids are insoluble fibrous protein aggregations sharing specific structural traits. ... Italic text // ahh addiing sum spiice iin hurr`` For other uses, see Brain (disambiguation). ... Dementia with Lewy bodies is the second most frequent cause of hospitalization for dementia, after Alzheimers disease. ... Inclusion body myositis (IBM) is an inflammatory muscle disease, characterized by slowly progressive wasting and weakness of the arms and legs. ... Congophilic angiopathy is a condition in which the same amyloid protein associated with Alzheimers disease (Amyloid beta) is deposited in the walls of the blood vessels of the brain. ... Protein folding is the process by which a protein assumes its characteristic functional shape or tertiary structure, also known as the native state. ... A prion (IPA: [1] ) — short for proteinaceous infectious particle (-on by analogy to virion) — is a type of infectious agent composed only of protein. ...

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be processed by α-, β- and γ-secretases; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39-43 amino acid residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleavage in the trans-Golgi network.^[1]. The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.^[2] Peptidases (proteases [pronounced pro-tea-aces] and proteolytic enzymes are also commonly used) are enzymes which break peptide bonds of proteins. ... The metal-binding domain of APP with a bound copper ion. ... A transmembrane protein is a protein that spans the entire biological membrane. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. ... β-secretase — also called BACE1 (β-site of APP cleaving enzyme) or memapsin-2 — is an aspartic-acid protease important in the pathogenesis of Alzheimers disease. ... 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. ... The C-terminal end refers to the extremity of a protein or polypeptide terminated by an amino acid with a free carboxyl group (COOH). ... Phenylalanine is one of the standard amino acids. ... The endoplasmic reticulum or ER is an organelle found in all eukaryotic cells that is an interconnected network of tubules, vesicles and cisternae that is responsible for several specialized functions: Protein translation, folding, and transport of proteins to be used in the cell membrane (e. ... Diagram of the endomembrane system in a typical eukaryote cell Micrograph of Golgi apparatus, visible as a stack of semicircular black rings near the bottom. ...

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease, likely as a result of altered proteolytic processing. Increases in either total Aβ levels or the relative concentration of both Aβ₄₀ and Aβ₄₂ (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques)^[3] have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due its more hydrophobic nature, the Aβ₄₂ is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril. For the scientific journal Heredity see Heredity (journal) Heredity (the adjective is hereditary) is the transfer of characters from parent to offspring, either through their genes or through the social institution called inheritance (for example, a title of nobility is passed from individual to individual according to relevant customs and... Familial Alzheimers disease (FAD) is an uncommon form of Alzheimers disease that comes on earlier in life, defined as before the age of 65 (usually between 30 and 65 years of age) and is inherited in an autosomal dominant fashion. ... Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion. ... Any projection from the cell body of a neuron can be referred to as a neurite. ... Etiology (alternately aetiology, aitiology) is the study of causation. ...

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.^[4] Tau proteins are normal proteins found within the brain. ...

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:^[5]

• β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
• γ-Secretase inhibitors. These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
• Selective Aβ-42 lowering agents. These modulate γ-secretase to reduce Aβ-42 production in favor of other (shorter) Aβ versions.
• Immunotherapies. These stimulate the host immune system to recognize and attack Aβ or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.
• Anti-aggregation agents. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.

β-secretase — also called BACE1 (β-site of APP cleaving enzyme) or memapsin-2 — is an aspartic-acid protease important in the pathogenesis of Alzheimers disease. ... HIV protease in a complex with the protease inhibitor ritonavir. ... 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. ...

Measuring Amyloid beta

There are many different ways to measure Amyloid beta. One highly senstive method is ELISA which is a immuno-sandwhich assay which utilizes a pair of antibodies that recognize Amyloid beta. Another, highly sensitive technology is AlphaLISA which is a no wash ELISA technology based on antibody coated beads. Elisa (born Elisa Toffoli on 19 December 1977) is an Italian singer and solo artist, writing and performing within several genres, notably rock, blues, soul and ambient. ... Wikipedia does not yet have an article with this exact name. ...

External link

• Mendelian Inheritance in Man (OMIM) 104300

The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ...

References