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Figure 10-E-1. Generation of the beta amyloid (Ab) from its precursor protein APP. The APP gene is located on chromosome 21. It is expressed by alternative splicing, generating three different isoforms, with 695, 751, and 770 residues, respectively. The sequence numbering in this figure refers to the 770 isoform. APP is a transmembrane protein, with a long extracellular region and a short intracellular region. It contains three proteolytic cleavage sites for a-, b- and g-secretase, respectively. The sequential cleavages by b- and g-secretases will generate the beta amyloid (Ab). If APP is cut by a-secretase, no Ab will be generated, since its cleavage site is located in the middle of the Ab region. Mutations of APP around the positions 670, 693 and 715 have been found to increase the risk of Alzheimer's disease. The position 670 is near the b-secretase cleavage site (Ab starts from D672). A double mutation at K670 and M671 increases the production of both Ab40 (with 40 residues) and Ab42 (with 42 residues). Mutations near the g-secretase cleavage site favors the production of Ab42. The effects of the mutations around E693 is more complicated (review). The g-secretase cleavage site is located in the membrane, which is unusual and more difficult. It is suggested (reference) that the substrate may need to associate with sphingolipids and cholesterol to increase the stability. Recently, it was found that the Ab protein indeed contains a sphingolipid binding domain (reference). This model can also explain why lowering cholesterol level can reduce the production of Ab proteins.
Review Article: Take five: BACE and the g-secretase quartet conduct Alzheimer's amyloid ß-peptide generation - EMBO J., 2004.
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