Intracellular Compartments and Ab Generation Involvement of Lipid Rafts

The broad intracellular distribution of the key proteins involved in Ab generation has made it difficult to identify the intracellular site where this event occurs. APP is distributed predominantly in the TGN, but significant amounts of the protein are found at the cell surface and within endosomes [88]. BACE has been placed within the early endosomes and/or throughout the endosomal-lysosomal system [88,89], although a predominant TGN localization has also been reported [90,91]. Finally, recent evidence suggests that presenilins are located primarily not only in the ER and Golgi apparatus but also on the plasma membrane and in the endosomes [90-92]. In addition to these different localizations, many reports indicate that APP, b-secretase and presenilin 1 all reside in rafts [86,93-95]. These findings led to the proposal that lipid rafts may be a site for the proteolytic processing of APP [96,97] (Fig. 10.3A). However, the observation that APP is present in DRMs from brain tissue at levels no higher than several other non-DRM proteins questions the involvement of lipid rafts in APP proteolytic processing.

The conflicting reports about the presence of APP in DRMs could be explained by reasoning that APP in DRMs is rapidly processed such that the steady-state amount of raft-associated protein is lower than it would otherwise be expected. However, it is possible that APP cleavage occurs outside rafts but that, after its generation, the Ab peptide rapidly translocates to the DRM after it is cleaved from APP because it has a high affinity for cholesterol [98] and ganglioside GM1

Fig. 10.3 Two different models for P-secretase processing of APP. (A) In neuronal APP-over-expressing cells, two cellular pools of both APP and BACE1 are present at the plasma membrane: one raft-associated and another outside rafts. Rafts are small and highly dispersed at the cell surface, and because they contain only a few proteins it is likely that APP and BACE1 are localized in separate rafts at the plasma membrane. Endocytosis is an essential step for APP- and BACE1-rafts to cluster and allow P-cleavage. In this model strong cholesterol depletion alters APP and BACE1 raft-association causing inhibition of

Fig. 10.3 Two different models for P-secretase processing of APP. (A) In neuronal APP-over-expressing cells, two cellular pools of both APP and BACE1 are present at the plasma membrane: one raft-associated and another outside rafts. Rafts are small and highly dispersed at the cell surface, and because they contain only a few proteins it is likely that APP and BACE1 are localized in separate rafts at the plasma membrane. Endocytosis is an essential step for APP- and BACE1-rafts to cluster and allow P-cleavage. In this model strong cholesterol depletion alters APP and BACE1 raft-association causing inhibition of

AP formation. (B) In an alternative model, the P-cleavage of APP should occur outside lipid rafts, as APP is mainly distributed in non-raft domains (a). In this model, the amy-loid-P is physiologically produced, but under mild cholesterol reduction (b) raft disorganization occurs and this process facilitates the close contact between APP and BACE1, leading to P-cleavage and a higher production of AP. Under strong cholesterol depletion (c), although BACE1 can more easily encounter APP, its activity is repressed because of raft disruption, and consequently AP production is inhibited.

[99,100], both of which are enriched in DRM [62,101] (Fig. 10.3B). Although depleting cells of cholesterol with mbCD has been shown to decrease the production of Ab [102], this effect may not be entirely due to the disruption of lipid rafts, because such treatment also disrupts clathrin-coated pits [103] in which APP has been localized [104] (see below).

Rafts could also be involved in the formation of amyloid fibrils, that are one of the pathological hallmarks of AD [105]. The molecular mechanism of amyloid fibril formation involves a major conformational transition of Ab, from a-helix to b-sheet [3], thus resembling the PrPc-PrPSc transconformation. In the case of AD, the conformational change required for the conversion of soluble peptide into amyloid fibrils is modulated by pH, Ab concentration and alteration in the primary sequence of Ab. In addition, two raft lipids (GM1 and cholesterol) bind to Ab and promote fibril formation [86,106]. Furthermore, synthetic lipid vesicles from bovine brain containing gangliosides such as GM1 bind to Ab, inducing an increased amount of a-helix at pH 7 and b-sheet at pH 6 [107]. It has also been demonstrated that a conformationally altered form of Ab, which acts as a "seed" for amyloid fibril formation, is generated in cholesterol-rich microdomains [108]. These findings support the view that lipid rafts could participate in the generation of Ab, and that raft lipids could modulate its conformation.

Moreover, since a sphingolipid-binding domain similar to the V3-like domain of PrP has been identified in Ab, APP and prion proteins might interact with lipid rafts by a common mechanism [109]. The molecular model proposed in Figure 10.1 to explain the role of lipid rafts in the PrPc to PrPSc conversion might also apply for Ab: in particular, evidence from biochemical, genetic and in-vivo studies has indicated that apolipoprotein E (apoE) seems to act as a pathological chaperone in AD amyloidogenesis, promoting fibril formation by inducing or stabilizing b-sheet conformation [3].

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