Amyloid beta

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Processing of the amyloid precursor protein
amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Identifiers
Symbol	APP AD1
HUGO	620
Entrez	351
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.

Contents 1 Formation 2 Intervention strategies 3 External link 4 References

[edit] Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP) by the β- and γ-secretases. γ-secretase produces Aβ₄₂ if cleavage occurs in the endoplasmic reticulum and Aβ₄₀ if the cleavage is in the trans-Golgi network.^[1]. APP is a transmembrane glycoprotein. 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)^[2] 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.

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.^[3]

[edit] Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:^[4]

• 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.

[edit] External link

• Mendelian Inheritance in Man (OMIM) 104300

[edit] References