The Role of Caveolae Rafts in gSecretase Activity

The g-secretase complex was also shown to be associated with rafts [131,132], mainly in the late-Golgi and post-Golgi-derived vesicles as well as in recycling endosomes, but not in plasma membrane rafts [95,132,133].

A recent report showed that despite g-secretase cleavage occurring in lipid rafts, g-secretase catalytic activity is independent of the presence of cholesterol [133,134]. Indeed, although biochemical assays in neuronal cells showed mature g-secretase to be associated with lipid rafts in a cholesterol-dependent manner when cholesterol was acutely depleted using mbCD, the quantities of Ab produced were not altered.

In addition, it has been proposed that g-cleavage of APP could also occur following endocytosis, resulting in the intracellular generation of Ab that could be either retained in intracellular compartments or released from recycling endosomes [115]. This balance of intracellular versus cell-surface Ab generation could be regulated by the half-life of APP at the cell surface.

The current data therefore support two different possibilities for APP g-cleav-age:

• g-cleavage occurs within cholesterol-rich lipid rafts in an intracellular compartment such as early/recycling endosomes, late-Golgi and post-Golgi-derived vesicles; or

• g-cleavage of APP occurs at the cell surface outside rafts (see Fig. 10.4).

222 | 10 Lipid Rafts in Trafficking and Processing of Prion Protein and Amyloid Precursor Protein 10.4.6

Essentials of Human Physiology

Essentials of Human Physiology

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