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amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Processing of the amyloid precursor protein
Identifiers
Symbol	APP
Alt. symbols	AD1
NCBI gene	351
HGNC	620
OMIM	104760
RefSeq	NM_000484
UniProt	P05067
Other data
Locus	Chr. 21 q21.2
Search for Structures Swiss-model Domains InterPro

Amyloid beta (Aβ or Abeta) is a peptide of 39–43 amino acids that appear to be 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. Research on laboratory rats suggest that the two-molecule, soluble form of the peptide is a causative agent in the development of Alzheimer's and that the two-molecule form is the smallest synaptotoxic species of soluble amyloid beta oligomer

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein, 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. 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.

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) have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to 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.

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.

Intervention strategies

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

• β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
• γ-Secretase inhibitors (e. g. Semagacestat). 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 Aβ₄₂ lowering agents (e. g. Tarenflurbil). These modulate γ-secretase to reduce Aβ₄₂ 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.

There is some indication that supplementation of the hormone melatonin may be effective against amyloid.

Measuring amyloid beta

There are many different ways to measure Amyloid beta. One highly sensitive method is ELISA which is an immuno-sandwich assay which utilizes a pair of antibodies that recognize Amyloid beta.

Imaging compounds, notable Pittsburgh Compound-B, (BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.

External links

• Online Mendelian Inheritance in Man (OMIM): 104300

References

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9. Michael H. Parker, Robert Chen, Kelly A. Conway, Daniel H. S. Lee; Chi Luoi, Robert E. Boyd, Samuel O. Nortey, Tina M. Ross, Malcolm K. Scott, Allen B. Reitz (2002). "Synthesis of (+)-5,8-Dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydro-naphthalene: An Inhibitor of β-Amyloid_1-42 Aggregation". Bioorg. Med. Chem. 10 (11): 3565–3569. doi:10.1016/S0968-0896(02)00251-1. PMID 12213471.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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• Genes on human chromosome 21
• Molecular neuroscience
• Enzymes
• Integral membrane proteins
• Alzheimer's disease