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In this chapter we have examined the intracellular routing and processing of PrPc and APP, and have discussed the possible intracellular sites of prion conversion and Ab generation. Because the intracellular trafficking and processing of prion proteins have crucial roles in prion conversion, it is believed that investigations of the different stages of intracellular trafficking and processing of prion proteins, together with an analysis of the cellular site involved in the conformational changes, will help to clarify the mechanisms which regulate prion formation.

Current data suggest that the ER might play a major role in the conversion of mutant PrP, whilst in the infectious diseases it is the transport of PrPc to the plasma membrane and its subsequent internalization that appear to be require-

ments for conversion. Furthermore, lipid rafts with which both PrPc and PrPSc are associated also appear to be fundamental for the conversion process. There are clear indications that rafts play an important role in stabilizing PrPc conformation, thereby exerting a protective role for the disease (see Fig. 10.2). They also appear to play a crucial role in the pathogenesis of Alzheimer's disease.

In particular, current evidence indicates that APP a-cleavage could occur both at the cell surface and intracellularly. Although some of the a-secretases have been localized in caveolae, the majority of this cleavage seems to occur outside rafts. Nonetheless, it is clear that membrane and raft integrity play major roles in controlling the balance between a- and P-cleavage which compete for the same substrate. Indeed, a moderate or drastic cholesterol depletion could affect the levels of these cleavages in different ways, leading to an increment of one or the other secretase processing, and thereby either incrementing or reducing AP production (see Fig. 10.3B). The manner in which this occurs and the nature of the major players is not completely clear, however.

A more meticulous analysis of lipid raft composition, together with the application of new methods to investigate the specific location of PrP and APP/AP in living cells and to reveal conformational changes within the molecules should provide a better understanding of prion and AP generation. This will lead to a better understanding of the pathogenesis of prion and Alzheimer's diseases, and possibly also to the development of new drugs for the prevention and therapy of these conditions.

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