APP processing pathway
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APP is a type-1 integral transmembrane protein in which the C-terminal portion of Aβ is embedded within the cell membrane. APP processing results in or precludes formation of the amyloidogenic Aβ peptide.
Cleavage by the membrane-associated metalloprotease α-secretase, the activity of which is probably manifested by several distinct enzymes, occurs within the Aβ domain (between residues 16 and 17), thereby preventing the formation of Aβ, and instead results in the release of the large soluble extracellular N-terminal portion of APP (APPsα) and a C-terminal fragment consisting of 83 residues (C83).
C83 might undergo further processing by γ-secretase to release the p3 peptide, which is considered non-amyloidogenic, although it is deposited in diffuse plaques.
To form Aβ, APP must undergo two sequential endoproteolytic steps, elaborated by distinct enzymatic activities known as β- and γ-secretase.
β-Secretase, which is the enzyme known as BACE1 (β-site APP-cleaving enzyme), cleaves APP at the N-terminal region of the Aβ sequence. Cleavage by β-secretase generates a slightly shorter soluble N-terminus (APPsβ) and the amyloidogenic C-terminal fragment (C99).
The cleavage of C99 by γ-secretase liberates the C-terminal 50 residues of APP, which is known as APP intracellular domain (AICD) and Aβ.