Amyloid precursor protein
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.
Cleavage products (there are 14) have many names including:
- Soluble APP-alpha (S-APP-alpha)
- Soluble APP-beta (S-APP-beta)
- Beta-amyloid protein 42 (Beta-APP42)
- Beta-amyloid protein 40 (Beta-APP40)
- Gamma-secretase C-terminal fragment 59(amyloid intracellular domain 59, AICD-59, AID(59), gamma-CTF(59))
- Gamma-secretase C-terminal fragment 57 (amyloid intracellular domain 57, AICD-57, AID(57), gamma-CTF(57))
- Gamma-secretase C-terminal fragment 50 (amyloid intracellular domain 50, AICD-50, AID(50), gamma-CTF(50))
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).
- ↑ Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 2015 Sep 10; 525(7568):247-50.(Link to article – subscription may be required.)
- ↑ Watts JC, Condello C, Stöhr J, Oehler A, Lee J, DeArmond SJ, Lannfelt L, Ingelsson M, Giles K, Prusiner SB. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. Proceedings of the National Academy of Sciences of the United States of America. 2014 Jul 15; 111(28):10323-8.(Link to article – subscription may be required.)