Several reports support the view that a-secretase-mediated cleavage of APP occurs on the cell surface [116,117,120-122]. Furthermore, a recent report showed that in non-neuronal cells APP is enriched within caveolae and is physically associated by its cytoplasmic domain with caveolin-1 . The C-terminal fragment resulting from APP processing by a-secretase is also localized within caveolae-enriched fractions. Importantly, in AD caveolae dysfunction may cause reduced activity of a-secretase and accumulation of toxic Ab, and caveolin depletion by antisense oligonucleotides prevented a-cleavage. On the other hand, caveolin overexpression increased the a-secretase-mediated proteolysis of APP , strongly suggesting that a-cleavage could occur in caveolae (Fig. 10.4). However, proteinase inhibitors added to the cell surface had no effect on APP cleavage, indicating that the bulk of the processing takes place intracellularly [123-125]. Therefore, a second mechanism should exist that involves an intracellular compartment which may be independent of the plasma membrane caveolae. Alternatively, this phenomenon could be explained by the presence of an intracellular form of caveolae - that is, plasma-lemmal vesicles. Thus, the a-secretase processing of APP could be regulated by the cycle of caveolae internalization and recycling. Because a-secretase cleavage occurs at both Leu17 and Val18 in the amyloid peptide , it is also possible to speculate on the existence of multiple a-secretases which cleave APP at distinct a-sites.
APP is known to transit through clathrin-coated pits and vesicles on its way to endosomes and lysosomes . It is therefore conceivable that a pool of APP is localized in caveolae where a-secretase processing takes place, whereas the remaining intact APP may be cleared from the cell surface via clathrin-coated pits and targeted to endosomes and lysosomes for proteolysis (Fig. 10.4).
Furthermore, Kojro et al.  found that small amounts of the ADAM10 (with a-secretase activity on APP) immature proform were associated with rafts in human embryonic kidney (HEK) cells and that cholesterol depletion by mbCD increased a-secretase activity. Similarly, filipin treatment, which causes the destruction of caveolar structures, also led to a substantial increase in a-secretase activity.
These data indicate that only a "minor part" of APP could be cleaved by the a-secretase within lipid rafts or caveolae microdomains. Moreover, fluorescence ani-sotropy studies and biochemical assays  indicate that increased membrane fluidity and impaired APP internalization are responsible for the increased a-secretase activity after acute cholesterol depletion by treatment with mbCD. Specifically, increased membrane fluidity could increase the lateral movement of APP and the a-secretase activity within the membrane.
Ledesma et al.  have shown that plasmin (a serine protease), which is present exclusively in lipid rafts of hippocampal neurons in culture, participates in APP a-processing directly or through the activation of other proteases (i. e., ADAM 10 ). Reduced brain plasmin could be one cause of amyloid plaque formation, since first, plasmin levels are low in brains affected by AD and some aged humans, and second, activation of plasmin increases the a-processing of APP and decreases the levels of Ab peptide .
Thus, the formation of amyloid plaques during senescence can be a consequence of a natural decrease in levels and/or activity of plasmin-mediated a-cleav-age of APP. Genetic predisposition and environmental factors would determine who suffers down-regulation of plasmin throughout life.
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