Amyloid precursor protein

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Amyloid precursor protein is the 770 amino acid protein chain which is a precursor to β-amyloid, abnormal local disposition of which is associated with Alzheimer's disease and some forms of cerebral amyloid angiopathy. Its processed form functions as a membrane receptor that has important roles in neuron growth, adhesion and axonogenesis. It is coded by the APP gene at 21q21. Abnomalities can cause inherited early onset dementia and some forms of cerebral amyloid angiopathy. They can also modify susceptibility to Alzheimer's disease. An extra copy of APP is present in Down's syndrome (trisomy 21) and may contribute to the increased incidence of Alzheimer's disease in this condition. Some splice isoforms have protease inhibitor activity. During maturation, the immature amyloid precursor protein is N-glycosylated in the endoplasmic reticulum and moves to the Golgi complex where complete maturation occurs with it being O-glycosylated and sulfated. There are extracellular copper binding sites (one close to the membrane can also binds zinc).

β-amyloid (Aβ)is formed by enzymatic cleavage of mature amyloid precursor protein. These enzymes are known as secretases. In normal cells, α-secretase cleaves APP through the A&beta section itself (non-amyloidogenic production), precluding its production by the other two enzymes, β- and γ-secretase. β-secretase cleaves APP to produce the C-terminus of Aβ while γ-secretase produces the N-terminus (its cleavage site can vary). In normal individuals, the Aβ peptide found in cerebrospinal fluid is formed from 39 or 40 amino acid residues, designated Aβ39/40. This is the form that is found in Aβ vascular amyloid, while a longer, less soluble 42/43 amino acid form is found in plaque amyloid (Aβ42/43). It has been postulated that some Aβ has prion like properties[1][2].

Cleavage products (there are 14) have many names including:

  1. N-APP
  2. Soluble APP-alpha (S-APP-alpha)
  3. Soluble APP-beta (S-APP-beta)
  4. C99
  5. Beta-amyloid protein 42 (Beta-APP42)
  6. Beta-amyloid protein 40 (Beta-APP40)
  7. C83
  8. P3(42)
  9. P3(40)
  10. C80
  11. Gamma-secretase C-terminal fragment 59(amyloid intracellular domain 59, AICD-59, AID(59), gamma-CTF(59))
  12. Gamma-secretase C-terminal fragment 57 (amyloid intracellular domain 57, AICD-57, AID(57), gamma-CTF(57))
  13. Gamma-secretase C-terminal fragment 50 (amyloid intracellular domain 50, AICD-50, AID(50), gamma-CTF(50))
  14. C31

At least 11 isoforms exist in vivo. Isoform APP695 is the predominant form in the CNS, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells with isoform APP751 common in T-lymphocytes.

Early onset Alzheimer disease 1 (AD1 OMIM:104300) is caused by several different variants of APP. Other variants cause APP-related cerebral amyloid angiopathy (CAA-APP, OMIM:605714). Both conditions are associated with transmembrane, cytoplasmic amino acid variation or extracellular variation close to the transmembrane amino acids (700-723).

References