Amyloid precursor protein (APP)、淀粉樣前體蛋白

Definition

Amyloid precursor protein (APP) is a single transmembrane protein that undergoes sequential proteolysis to generate multiple peptides, including the amyloid beta peptide the major component of the senile plaques that are diagnostic hallmarks of Alzheimer disease (AD).

Discovery

In 1984, Glenner and Wong purified APP derived from the twisted beta-pleated sheet fibrils present in cerebrovascular amyloidoses and in the amyloid plaques associated with Alzheimer disease1.

Structural characteristics

APP is a 110-130 kDa, transmembrane cell surface glycoprotein, which contains N and O, linked sugars. The largest region of the molecule is the extracellular domain. This domain contains a cysteine-rich region of about 200 amino acids and is at the N-terminus of the protein. It has a single membrane-spanning domain towards the carboxyl terminus and a short cytoplasmic tail. APP contains a domain very similar to the Kunitz family of serine protease inhibitors and the APP protein is homologous to protein protease nexin-II2.

Mode of action

APP plays an essential role in the reduction of copper II to copper I. This electron transfer reaction is involved in the formation of reactive oxygen species (e.g., superoxide radical and hydroxyl radical)3 which are extremely reactive with many different cellular components. These reactions can produce large amounts of damage and ultimately results in cell death.

Function

APP plays major roles in the regulation of several important cellular functions, especially in the nervous system, where it is involved in synaptogenesis and synaptic plasticity. The secreted extracellular domain of APP, sAPPa, acts as a growth factor for many types of cells and promotes neuritogenesis in post-mitotic neurons4.

References

1. Furuya H, Sasaki H, Goto I, Wong CW, Glenner GG, Sakaki Y. (1988). Amyloid beta-protein gene duplication is not common in Alzheimer's disease: analysis by polymorphic restriction fragments. Biochem Biophys Res Commun., 150 (1):75-81.

2. Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F (1988). A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature, 331 (6156):525-527.

3. Camakaris J, Voskoboinik I, Mercer JF (1999). Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun, 261:225-232.

4. Gralle M, Ferreira ST (2007). Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Prog Neurobiol, 82 (1):11-32.