• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Biochim Biophys Acta. Author manuscript; available in PMC Aug 1, 2011.
Published in final edited form as:
PMCID: PMC2886169

Membrane rafts in Alzheimer’s disease beta-amyloid production


Alzheimer’s disease (AD), the most common age-associated dementing disorder, is pathologically manifested by progressive cognitive dysfunction concomitant with the accumulation of senile plaques consisting of amyloid-β (Aβ) peptide aggregates in the brain of affected individuals. Aβ is derived from a type I transmembrane protein, amyloid precursor protein (APP), by the sequential proteolytic events mediated by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Multiple lines of evidence have implicated cholesterol and cholesterol-rich membrane microdomains, termed lipid rafts in the amyloidogenic processing of APP. In this review, we summarize the cell biology of APP, β- and γ-secretases and the data on their association with lipid rafts. Then, we will discuss potential raft targeting signals identified in the secretases and their importance on amyloidogenic processing of APP.

Keywords: Alzheimer’s disease, amyloid, amyloid precursor protein, cholesterol, palmitoylation, lipid rafts

1. Introduction

Alzheimer’s disease (AD) is one of the major neurodegenerative diseases that is predominant among aged individuals. The principal pathological hall marks of AD, originally described by Alois Alzheimer a little over one hundred years ago, are the two lesions, neurofibrillary tangles and senile plaques, which are found at significantly higher frequency in the cortex and hippocampus in individuals afflicted with AD compared to age matched healthy individuals [1]. Eighty years later, the molecular composition of senile plaques was deciphered with the advent of advanced biochemical and genetic tools. Senile plaques consist of extracellular deposits of 39–42 amino acid-long amyloid-β (Aβ) peptides. Subsequent studies revealed that Aβ is released from a large type I transmembrane protein, termed amyloid precursor protein (APP), by the sequential proteolysis of a set of enzymes termed β- and γ-secretases. Identification of familial AD linked mutations in APP gene launched the exploration of the cell biology of APP and these secretases to modulate Aβ production to attenuate disease pathology. A growing body of evidence indicates that changes in cholesterol homeostasis can influence Aβ production, and studies in neuronal and non-neuronal cells implicate cholesterol-enriched membrane microdomains, termed lipid rafts, in amyloidogenic processing of APP. However, the connection between cholesterol, lipid rafts and APP processing has not been completely understood, and controversy still exists. In this review, we will first describe the cell biology of APP, β- and γ-secretases followed by the mechanistic details of amyloidogenic processing. Then, we will elaborate on the current status of research addressing the importance of raft association of BACE1 and γ-secretase, and discuss potential raft targeting signals in the secretases and their unanticipated redundant role on amyloidogenic processing of APP.

2. Cell biology of APP, secretases and APP processing

2.1. An overview of APP and secretases

The APP gene is mapped to chromosome 21 and different isoforms of APP exist as a result of alternative splicing of the nascent transcript. Predominant isoforms include APP695, 751 and 770 which differ by the absence (APP695) or presence (APP751 and 770) of an extracellular Kunitz protease inhibitor (KPI) domain. APP695 is the major neuronal isoform whereas APP770 isoform is expressed in most other cell types. Direct correlation of APP overexpression and AD pathology is evident in Down’s syndrome in which trisomy of chromosome 21 results in an extra copy of the APP gene. Despite the fact that normal physiological function of APP is still unclear, many putative functions have been ascribed that include regulation of neurite outgrowth, cell adhesion, synaptogenesis and cell survival. Although APP knockout mice are viable, they develop impairments in spatial learning and long-term potentiation (LTP) [2].

Aβ is released from the precursor, APP by a two step cleavage process involving two proteases, which is refered to as the amyloidogenic processing of APP. β-secretase cleaves APP in the lumenal domain proximal to the transmembrane segment and generates the N-terminus of Aβ. γ-secretase mediates the cleavage that generates the C-terminus of Aβ. In addition to these two secretases, a third enzyme activity termed α-secretase, initiates non-amyloidogenic processing of APP. Because the later enzyme activity cleaves within the Aβ domain, cleavage by α-secretase precludes the generation of intact Aβ. Interestingly, all three secretases are transmembrane proteases: β-site APP-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease [3]; α-secretase activity is associated with at least three members of the ADAM (a disintegrin and metalloprotease) family (ADAM9, ADAM10 and ADAM17) [4]; and γ-secretase is a multiprotein complex comprising four core subunits that are each transmembrane proteins—presenilins (PS1 or PS2), nicastrin, PEN2 and APH1 [5].

2.2. APP processing

APP, β- and γ-secretases are the three principal players involved in Aβ production. Amyloidogenic processing is initiated by BACE1 cleavage of APP, which results in the release of the large soluble ectodomain (APPsβ) and a membrane-tethered C-terminal fragment (β-CTF). The second cleavage is mediated by γ-secretase, which cuts β-CTF within the transmembrane domain to release Aβ into the extracellular milieu and the APP intracellular domain into the cytoplasm. γ-secretase cleaves at multiple sites within the transmembrane segment of APP due to its heterogenous site preference, thus generating variable length (39-42 amino acid long) Aβ peptides. The longer forms of Aβ are prone to rapid aggregation, oligomerization and fibril formation, events that are thought to be critical for the development of AD pathology. Non-amyloidogenic processing of APP is initiated by α-secretases, which cut APP at the lumenal domain at 16 amino acids downstream of BACE1 cleavage site, also releasing a soluble ectodomain of APP (APPsα) and generating a truncated CTF (α-CTF) that is then cleaved by γ-secretase. Because α-secretase cleavage truncates the N-terminus of Aβ, non-amyloidogenic processing pathway results in the generation of N-terminally truncated Aβ peptides, refered to as p3 peptides. Amyloidogenic and non-amyloidogenic processing of APP are mutually exclusive and commitment of APP into these pathways depends on the cellular levels of α- and β-secretases. While α-secretase processing is predominant in non-neuronal cells, APP is mainly channeled into the amyloidogenic pathway in neurons as a consequence of high abundance of BACE1 in neuronal cells [6]. Proteolytic processing of APP per se is a highly regulated event and additional regulatory components of secretases have been identified. Given that α- and β-secretases compete with each other for APP processing and have opposing effects on Aβ generation, deciphering the signaling pathways and molecular events involved in the commitment of APP to these pathways has high therapeutic potential. APP is not the sole physiological substrate for BACE1 and γ-secretase. Additional BACE1 substrates have been identified by candidate approaches that include APP-like proteins (APLP1 and APLP2), β-galactoside α, 2,6-sialyltransferase, P-selectin glycoprotein ligand-1, low-density lipoprotein receptor-related protein (LRP), β subunits of voltage-gated sodium channels, interleukin-1 receptor II (IL-1R2) and neuregulin1 and 3 [613]. Recently, Hemming et al [14] identified 60 more BACE1 substrates based on unbiased proteomic approach. The majority of BACE1 substrates are type I membrane proteins. Interestingly, most of these substrates are involved in contact-dependent intercellular communications. Similarly, γ-secretase can mediate sequence-independent cleavage of a wide range of type I transmembrane proteins that undergo ectodomain shedding, including Notch receptors and ligands, the netrin receptor DCC, the receptor tyrosine kinase ErbB-4, and LRP, extending the physiological role of PS1 beyond the nervous system and AD pathogenesis [15]. Additional substrates of γ-secretase were identified recently by an unbiased proteomic study; dystroglycan, the Delta/Notch like EGF-related receptor, desmoglein-2, natriuretic peptide receptor-C, plexin domain containing protein 2, and vasorin [16]. Given the fact that the list of BACE1 and γ-secretase substrates continues to grow, potential strategies to target BACE1 or γ-secretase activity will have to consider—and incorporate rational means to avoid—potential adverse consequences resulting from total inhibition of BACE1 and γ-secretase processing of diverse substrates.

2.3. Secretases cleave APP in diverse cellular compartments

The efficiency of APP processing to Aβ is greatly affected by its subcellular localization, and therefore the regulators of intracellular trafficking and subcellular localization of APP and the secretases have been extensively examined. APP is synthesized in the endoplasmic reticulum (ER) and is trafficked through the secretory pathway in a constitutive manner although only a small fraction of APP (~10%) arrives at the plasma membrane. APP is modified by the addition of N- and O-linked oligosaccharides, tyrosine sulfation and phosphorylation during the transit in the secretory pathway en route to the plasma membrane [1722]. In cultured cells, at steady state, the majority of APP is localized in the Golgi apparatus, trans-Golgi network (TGN), and post-TGN vesicles. APP has a relatively short residence time at the cell-surface as it either undergoes α-secretase cleavage or becomes internalized into endosomes (Fig. 1) [23, 24]. A ‘YENPTY’ internalization motif located near the C-terminal tail of APP is responsible for its efficient endocytosis. Several adaptor proteins including X11/Mint, Fe65, Dab1, JIP family of proteins and Sorting nexin bind to the ‘NPTY’ motif within the cytoplasmic domain of APP and regulate its trafficking and, ultimately modulate APP processing to Aβ [2530]. In addition to cytosolic adaptors, several transmembrane proteins that include LDLR family members (LRP1, LRP1B and SorLA) also interact with APP, modulate its trafficking, and affect Aβ production [3133]. In neurons, APP is axonally transported via the fast anterograde transport machinery. As a consequence, one documented source of amyloid deposits is the synaptically released Aβ pool [15, 34]. The subcellular localization of APP processing to Aβ has been a topic of central importance. The majority of studies on localization of BACE1, γ-secretase and APP processing were performed in cultured cells, especially in non-neuronal cells such as CHO and HEK293 cells. In transfected cells, Aβ is mainly generated in the TGN and endosomes as APP is trafficked through the secretory and recycling pathways. This is consistent with the predominant localization of BACE1 and γ-secretase in these organelles. BACE1 is synthesized as a preproenzyme, the pro-domain of which is cleaved by furin-like protease as it is trafficked to the plasma membrane through the secretory pathway. BACE1 then cycles between the cell surface and endosomes, and at steady-state, the majority of BACE1 is found in the late Golgi–TGN compartments and endosomes [35]. The C-terminus of BACE1 has an acidic dileucine motif (495DDISLLK501) that targets BACE1 from plasma membrane to endosomes [35], and phosphorylation at Ser498 is implicated in trafficking between early endosomes and the TGN/late endosomes [36]. However, mutation of both of these trafficking signals did not influence BACE1 activity or Aβ production in overexpression studies [37]. Optimal activity of BACE1 at pH 4.5 in vitro implicates acidic organelles such as endosome as major sites of BACE1 cleavage of APP. Indeed, endocytosis of APP has been shown to be critical for Aβ production both in cultured cells and in vivo [38, 39]. BACE1 cleaves wild-type APP during transit in the endocytic pathway [38]. Interestingly, APP bearing mutations associated with familial early-onset AD in a Swedish kindred (APPSwe) is more readily cleaved by BACE1 in the secretory pathway, as early as during transit of nascent APP though the Golgi apparatus [40]. Cholesterol-enriched membrane microdomains termed lipid rafts has been implicated in BACE1 cleavage of APP (discussed below).

Fig. 1
Schematic illustration of intracellular itinerary of amyloid precursor protein (APP). Synthetic APP is trafficked through the constitutive secretory pathway to the plasma membrane (blue arrows). From the cell surface, a fraction of APP is internalized ...

γ-secretase is a multiprotein complex made of four integral membrane proteins that include PS1, nicastrin, APH1 and PEN2. The assembly of γ-secretase complex starts with the stabilization of nascent PS1 by nascent nicastrin and APH1. Subsequently, PEN2 enters this trimeric complex to complete the assembly process [5]. Gene knockout, knockdown and mutational studies have established that PS1 is the catalytic subunit of γ-secretase [4143]. Nicastrin has been proposed as the substrate binding subunit, but this notion has not yet gained wide acceptance. The subcellular localization of γ-secretase and its activity still remains controversial because subunits of this enzyme have been found in multiple organelles including ER, ER–Golgi intermediate compartments, Golgi apparatus, endosomes, lysosomes, phagosomes, plasma membrane, and mitochondria. By combining fractionation with non-ionic detergent extraction analysis, we found that γ-secretase subunits reside in cholesterol- and sphingolipid-rich detergent-resistant lipid raft microdomains of post-Golgi, TGN and endosome membranes (discussed below) [44].

3. Lipids and Alzheimer’s disease connection

3.1. The role of cholesterol in AD pathogenesis

Cholesterol has long been clinically associated with AD pathogenesis and this connection attracted many research groups to explore the underlying causal role of cholesterol on APP processing for therapeutic intervention. In fact, the brain is the most cholesterol-rich organ in our body, which can sequester 25% of total cholesterol even though it contributes to 2% of total body weight [45, 46]. Since, cholesterol is the main constituent of lipid rafts, it is imperative to understand the importance of lipid rafts in the central nervous system. Indeed, there is an increasing number of neurological functions attributed to lipid rafts that include neuronal cell signaling, adhesion and axon guidance [4749]. The importance of cholesterol in AD pathogenesis became evident from the following studies. First, the levels of total cholesterol and LDL in serum correlate with Aβ load in the brains of patients with AD [50]. Second, epidemiological evidence suggests that individuals with elevated cholesterol levels during mid-life tend to develop AD pathology [51]. Third, in retrospective studies, patients treated with statins, inhibitors of the hydroxymethyl glutaryl-coenzyme A (HMG) reductase (the rate-limiting enzyme in cholesterol synthesis), to lower their cholesterol showed significantly reduced prevalence and incidence of AD [52, 53]. In support of these results, elevated dietary cholesterol uptake has been found to increase amyloid plaque formation in rabbits [54]. Recently, however, the benefits of statins with respect to the incidence of AD or cognitive decline in patients with AD have been challenged [5557]. Furthermore, recent studies demonstrated that the commonly used cholesterol-lowering agent lovastatin is known to have cholesterol-independent effects on APP trafficking and processing [58, 59]. Fourth, cholesterol loading and depletion studies in cultured cells and in transgenic mouse models of AD found a correlation between cholesterol levels and the efficiency of Aβ production and deposition [6063]. Finally, in guinea pigs, as well as in transgenic mouse models of AD, treatment with cholesterol-lowering drugs markedly reduced Aβ deposition, demonstrating a positive correlation between plasma cholesterol levels and cerebral Aβ load [61, 63].

3.2. Lipids modulate amyloidogenic processing of APP

Abnormality in cellular distribution and transport of cholesterol have been causally linked to many neurodegenerative diseases that include Alzheimer’s disease, Smith–Lemli–Opitz syndrome, Huntington’s, and Niemann–Pick Type C diseases [6466]. In cell culture and animal experiments, alteration in subcellular cholesterol distribution has been found to modulate APP processing. Both secreted and intracellular Aβ were significantly reduced in neuronal cells when cholesterol transport from late endocytic organelles to the ER was blocked by the cholesterol transport inhibiting drug, U18666A [67]. Increased cholesterol efflux mediated by ATP-binding cassette transporter A1 decreases Aβ production by reducing BACE1 and γ-secretase cleavage of APP [68]. Cholesteryl esters, derived from free cholesterol by acyl-coenzyme A:cholesterol acyl transferase, have also been shown to modulate Aβ production [69]. Another study carefully examined the effect of statins, which lower the levels of cholesterol and nonsterol isoprenoids such as farnesyl pyrophosphate, and geranylgeranyl pyrophosphate, and showed that lowering cellular isoprenoid levels increased the intracellular pool of APP metabolites and Aβ [70]. Interestingly, supplementing mevalonate at a low level was sufficient to rescue statin-induced blockade of isoprenoid synthesis and prevent the increase in intracellular Aβ levels. These results suggest that cellular cholesterol and isoprenoid levels have independent effects on APP metabolism and Aβ production [70]. Sphingolipids, another major constituent of membrane raft domains are also involved in regulation of APP processing. Lowering sphingolipid levels either by inhibiting serine palmitoyltransferase, which is involved in the early step of sphingholipid biosynthesis, or by mutating one of the serine palmitoyltransferase enzyme subunits, elevates α-secretase cleavage [71]. Furthermore, secretion of Aβ42, but not Aβ40, was markedly elevated under these conditions, suggesting additional modulation of γ-secretase cleavage.

4. Amyloidogenic processing in lipid rafts

4.1 Lipid rafts

Lipid rafts are dynamic and highly ordered membrane microdomains rich in cholesterol and sphingolipids that are distinct from surrounding membranes of unsaturated phospholipids. The average size of lipid rafts is estimated to be 50 nm in diameter, although several distinct raft domains can exist in a cell that are heterogeneous in size and life time [72, 73]. Lipid rafts concentrate select proteins and serve as a platform for cellular processes such as cell signaling, pathogen entry, cell adhesion, motility, protein sorting and trafficking [72, 74]. At first, lipid rafts were biochemically defined as detergent-insoluble membrane (DIM) domains that resisted extraction with certain non-ionic detergents such as Triton X-100 and Lubrol WX at 4°C [75]. Now, there are several concerns about the use of detergent to study lipid raft localization of proteins in biological membranes, and other methods such as fluorescence visualization at nanoscale resolution are necessary to substantiate biochemical results [76]. A working definition of lipid rafts was developed at the 2006 Keystone Symposium on Lipid Rafts and Cell Function: “membrane rafts are small (10–200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein–protein and protein–lipid interactions”[77]. Although lipid rafts are highly abundant at plasma membrane, they are first assembled in the Golgi and are found in the anterograde vesicles trafficking from the Golgi to the plasma membrane in the biosynthetic pathway [75, 78]. On the other hand, retrograde vesicles from Golgi to ER have very little sphingolipid and cholesterol content [78]. Rafts are constantly endocytosed from plasma membrane through the endocytic pathway and either recycled back to plasma membrane or returned to Golgi apparatus [79, 80].

4.2. The role of lipid rafts in amyloidogenic processing of APP

Multiple lines of evidence implicates lipid rafts in amyloidogenic processing of APP. A subset of BACE1 and full length APP (APP FL) associates with lipid raft domains [81, 82]. Targeting the BACE1 lumenal domain to lipid rafts by the addition of a glycophosphatidylinositol anchor increases APP processing at the β-cleavage site [83]. Elegant work utilizing antibody-mediated co-patching of cell surface APP and BACE1 demonstrated that processing of APP into Aβ can be induced in raft microdomains [84]. Interestingly, however, Abad-Rodriguez et al. [85] reported that displacement of BACE1 from raft domains by moderate reduction of cholesterol promotes membrane proximity of BACE1 and APP in non-raft domains and increases β-cleavage of APP [85]. Each of the four core subunits of the γ-secretase complex are enriched in DIM fractions that are positive for bona fide lipid raft markers, flotillin-2 and prion protein [44]. More importantly, raft association of γ-secretase subunits is sensitive to acute cholesterol depletion, fulfilling a stringent criterion for determining lipid raft localization. Involvement of lipid rafts in amyloidogenic processing of APP by γ-secretase is also demonstrated by the increased accumulation of APP CTFs in lipid raft microdomains either by inhibition or absence of γ-secretase activity [44]. Studies using a combination of biochemical fractionation and magnetic immunoisolation, indicate that the γ-secretase complex co-resides in lipid raft microdomains with APP CTFs and SNARE proteins such as VAMP4 (TGN), syntaxin 6 (TGN and vesicles) and syntaxin 13 (early endosomes) [44, 82]. These studies indicate that γ-secretase processing of APP CTFs may be preferentially localized in lipid raft microdomains of post-Golgi and endocytic organelles. Interestingly, mature components of the γ-secretase complex are excluded from cell surface raft domains that are positive for SNAP-23. These results suggest that the relatively small amount of active γ-secretase complex present at the cell surface could be residing in non-raft membrane domains [44]. Interestingly, our studies also showed that spatial segregation of the γ-secretase complex in membrane rafts of intracellular organelles might limit the access to some of its diverse substrates [82]. For example, APP CTFs in adult brain and cultured cells preferentially enriched in raft microdomains, whereas several other substrates such as CTFs derived from Notch1, Jagged2, N-cadherin and DCC reside in non-raft membranes [82]. These findings reiterate the prediction that γ-secretase might preferentially cleave APP in lipid rafts.

5. Approaches to target raft associated amyloidogenic processing of APP

5.1. Cholesterol depletion

Selective targeting of BACE1 and γ-secretase processing of APP in lipid rafts is considered as an elegant therapeutic strategy to modulate Aβ production. Cholesterol is the main constituent of lipid rafts and depletion of cellular cholesterol by sequestering agent such as methyl-β-cyclodextrin disturb the integrity of lipid raft domains. Therefore, cholesterol depletion was used as an approach to displace secretases and APP from raft domains. As a consequence, APP processing to Aβ was strongly inhibited with a concomitant increase in α-secretase processing of APP, which does not involve lipid rafts [84]. These results however are difficult to interpret because the increase in α-secretase processing of APP may not be a direct consequence of loss of raft integrity, but possibly the end result of other mechanisms including accumulation of APP at the cell surface and altered membrane fluidity [86]. Further studies using cultured hippocampal neurons showed that depending on the extent of depletion, loss of cholesterol can either have a positive (<25% loss) or negative (>35% loss) effect on amyloidogenic processing of APP and therefore raised concerns on the use of cholesterol lowering drugs such as statin as an therapeutic approach to lower Aβ production [85]. Another critical issue that confounds proper interpretation of statin studies on Aβ production is the pleiotropic effects of cholesterol depletion on Golgi morphology and vesicular trafficking, which are an unexpected consequence of changes in both membrane fluidity and curvature [87, 88]. In addition, lovastatin has been shown to decrease cholesterol levels in the exofacial membrane leaflet and to reduce membrane bulk fluidity [89]. Taken together these studies necessitate better approaches for the displacement of APP or its secretases from raft domains in an attempt to reduce Aβ production.

5.2. Raft targeting signals in BACE1

A more realistic approach will be to identify the raft targeting signals in secretases and APP. The attachment of a glycophosphatidylinositol (GPI) group is responsible for raft targeting of proteins that are located on the extracellular face of the plasma membrane. Post-translational acyl modifications of proteins such as S-palmitoylation, N-myristoylation target variety of cytosolic and transmembrane proteins to lipid raft microdomains due to the high affinity of acyl chains for the ordered lipid environment within raft domains [90]. BACE1 undergoes S-palmitoylation at four Cys (Cys474/478/482/485) residues near the transmembrane and cytoplasmic boundary (Fig. 2) [91, 92]. Experimental mutation of these residues completely abolishes palmitoylation of BACE1 and prevents raft association of BACE1. Importantly, unlike the case in many other proteins, the lack of palmitoylation does not affect protein stability or subcellular localization of BACE1. Surprisingly however, displacement of BACE1 by abolishing S-palmitoylation neither affected BACE1 processing of APP nor the secretion of Aβ in cultured cell lines. These results indicate that S-palmitoylation-dependent raft targeting of BACE1 is dispensable for APP processing and the palmitoylation-deficient mutant of BACE1 can process APP as efficiently as wild type BACE1 [92]. To substantiate this conclusion, biochemical fractionation showed that there is a considerable shift in the distribution of APP CTFs into non-raft fractions in cells stably expressing palmitoylation-deficient BACE1 mutant, consistent with BACE1 processing of APP in non-raft domains.

Fig. 2
Raft targeting signals identified in BACE1 and γ-secretase subunits nicastrin and APH1. BACE1 is S-palmitoylated at four Cys residues (Cys474/478/482/485) located at transmembrane and cytoplasmic boundary. (B) S-palmitoylation of γ-secretase ...

5.3. Raft targeting signals in γ-secretase

Our earlier studies demonstrated that γ-secretase and APP CTFs co-reside in raft microdomains of late endosomes, the TGN, and TGN-derived vesicles and processing of other γ-secretase substrates is segregated from the APP processing in the raft domains [82]. As discussed above, displacement of BACE1 from lipid rafts by substitution of palmitoylation sites did not affect Aβ production. Irrespective of BACE1 processing of APP in raft (BACE1 wild type) or non-raft domains (BACE1 palmitoylation-defecient mutant), BACE1 cleaved APP CTFs eventually accumulate in lipid raft domains [92], and similarly α-secretase cleaved fragments (APP α-CTFs) in BACE1−/− fibroblasts also accumulate in lipid raft domains (our unpublished results). Furthermore, absence or inhibition of γ-secretase activity results in the accumulation of APP CTFs in raft domains [82, 93]. Together, these results strongly suggest that γ-secretase cleavage of α-CTF and β-CTF occurs in raft domains. Therefore, displacing either γ-secretase or its immediate substrate, APP CTFs from raft domains should theoretically be an effective strategy to reduce Aβ production by separating the enzyme away from the substrate. We recently identified potential raft targeting signals in γ-secretase subunits, nicastrin and APH1 [94]. Nicastrin is S-palmitoylated at cysteine residue (Cys689) in the transmembrane domain and APH1 undergoes S-palmitoylation at Cys182 and Cys245 that are oriented towards the cytosol (Fig. 2). Unlike the case of BACE1, S-palmitoylation contributes to the protein stability of nascent nicastrin and APH1. Interestingly, assembly of nicastrin and APH1 into the γ-secretase complex does not require palmitoylation, and the stability of palmitoylation-deficient nicastrin and APH1 that are already assembled in the γ-secretase complex is indistinguishable from that of the wild type subunits. Furthermore, palmitoylation of nicastrin and APH1 is required for raft association of these nascent subunits but did not affect the raft localization of PS1 and PEN2 or the assembled γ-secretase complex. Therefore, these studies imply the presence of additional dominant signals or interacting proteins that may target the fully assembled γ-secretase complex to rafts. In addition to lipid attachment, hydrophobic transmembrane domain residues in contact with the exoplasmic leaflet of the membrane have been implicated in raft association of proteins [95]. Protein–protein interactions also facilitate raft targeting of certain proteins, such as in the case of raft localization of glutamate receptor-interacting protein 2 through interaction with the C-terminus of the raft-resident transmembrane protein ephrin B1 [96]. Like in the case of BACE1, stable overexpression of these palmitoylation-deficient mutant subunits of nicastrin and APH1 did not affect amyloidogenic processing of APP and as well as other γ-secretase substrates. Thus the physiological significance of S-palmitoylation of APP secretases has not been completely understood.

5.4. Raft targeting signals in APP

Analysis of APP has revealed an interesting characteristic with reference to lipid raft association. Less than 10% of APP FL associate with lipid raft domains, whereas APP CTFs accumulate predominately in these domains. Therefore, the signals within the transmembrane domain or cytosolic tail of APP CTFs that promote raft association following ectodomain shedding of APP FL, remain to be identified. The available data indicate that APP association with lipid rafts is enhanced during endocytic trafficking [84]. APP interacting proteins which modulate Aβ production such as cytosolic adaptor proteins, Mint and Fe65 or transmembrane receptor proteins, LRP and SorLA may have a role on the segregation of APP CTFs into the rafts or the exclusion of APP FL from lipid raft domains. Interestingly, the cytoplasmic domain of LRP has been shown to facilitate the association of APP and BACE1 and enhances the delivery of APP in lipid rafts through the endocytic pathway [97]. Given the fact that a number of γ-secretase substrates are spatially segregated in non-raft domains [82], the rational design of inhibitors that target raft-localized γ-secretase seems to be promising and possibly preclude at least some of the potential side effects associated with the complete inhibition of γ-secretase.

6. Conclusion

The role of cholesterol in amyloidogenic processing of APP came under close scrutiny following the publication of epidemiological studies that correlated cellular cholesterol and AD pathogenesis. Given that cholesterol is one of the major constituent of lipid rafts, the involvement of raft membrane microdomains in APP processing was investigated. Indeed, multiple lines of evidence suggest that amyloidogenic processing of APP is associated with membrane raft microdomains. Spatial segregation of γ-secretase processing of APP from that of other substrates suggested targeting of APP processing in lipid rafts as a novel approach to selectively modulate Aβ production. Surprisingly, displacement of BACE1 by mutating raft targeting signals in this secretase did not affect the APP processing in cell culture studies. Similarly, raft targeting signals identified in γ-secretase complex subunits, nicastrin and APH1 neither affected the raft association of mature γ-secretase complex nor APP processing to Aβ. Thus the targeting signals that are primarily responsible for lipid raft association of γ-secretase and APP CTF await identification. Further investigation in this area could possibly provide a rational approach to pharmacologically target APP processing in lipid rafts.


Research in authors’ laboratories are supported by NIH grants AG021495 and AG019070, Alzheimer’s Association (IIRG to GT; NIRG to KSV) and the American Health Assistance Foundation.


amyloid precursor protein
presenilin (s)
β-site APP cleaving enzyme 1
C-terminal fragment
trans-Golgi network
detergent-insoluble membrane
Vesicle-associated membrane protein


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin. 1907;64:146–148.
2. Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283:29615–29619. [PMC free article] [PubMed]
3. Vassar R. BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci. 2004;23:105–114. [PubMed]
4. Allinson TM, Parkin ET, Turner AJ, Hooper NM. ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res. 2003;74:342–352. [PubMed]
5. Iwatsubo T. The g-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol. 2004;14:379–383. [PubMed]
6. Kitazume S, Tachida Y, Oka R, Shirotani K, Saido TC, Hashimoto Y. Alzheimer’s beta-secretase, beta-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc Natl Acad Sci U S A. 2001;98:13554–13559. [PMC free article] [PubMed]
7. Li Q, Sudhof TC. Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1. J Biol Chem. 2004;279:10542–10550. [PubMed]
8. Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, De Strooper B, Seed B. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem. 2003;278:48713–48719. [PubMed]
9. von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, Spoelgen R, Hshieh TT, Ranganathan S, Battey FD, Liu CX, Bacskai BJ, Sever S, Irizarry MC, Strickland DK, Hyman BT. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem. 2005;280:17777–17785. [PubMed]
10. Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N. beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem. 2005;280:23009–23017. [PubMed]
11. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520–1525. [PubMed]
12. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314:664–666. [PubMed]
13. Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF. Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem. 2007;282:11982–11995. [PubMed]
14. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4:e8477. [PMC free article] [PubMed]
15. Lazarov O, Lee M, Peterson DA, Sisodia SS. Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci. 2002;22:9785–9793. [PubMed]
16. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol. 2008;6:e257. [PMC free article] [PubMed]
17. Schubert D, LaCorbiere M, Saitoh T, Cole G. Characterization of an amyloid beta precursor protein that binds heparin and contains tyrosine sulfate. Proc Natl Acad Sci U S A. 1989;86:2066–2069. [PMC free article] [PubMed]
18. Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell. 1989;57:115–126. [PubMed]
19. Oltersdorf T, Ward PJ, Henriksson T, Beattie EC, Neve R, Lieberburg I, Fritz LC. The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem. 1990;265:4492–4497. [PubMed]
20. Suzuki T, Nairn AC, Gandy SE, Greengard P. Phosphorylation of Alzheimer amyloid precursor protein by protein kinase C. Neuroscience. 1992;48:755–761. [PubMed]
21. Knops J, Gandy S, Greengard P, Lieberburg I, Sinha S. Serine phosphorylation of the secreted extracellular domain of APP. Biochem Biophys Res Commun. 1993;197:380–385. [PubMed]
22. Oishi M, Nairn AC, Czernik AJ, Lim GS, Isohara T, Gandy SE, Greengard P, Suzuki T. The cytoplasmic domain of Alzheimer’s amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and cultured cells. Mol Med. 1997;3:111–123. [PMC free article] [PubMed]
23. Sisodia SS. Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci U S A. 1992;89:6075–6079. [PMC free article] [PubMed]
24. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science. 1992;255:728–730. [PubMed]
25. Miller CC, McLoughlin DM, Lau KF, Tennant ME, Rogelj B. The X11 proteins, Abeta production and Alzheimer’s disease. Trends Neurosci. 2006;29:280–285. [PubMed]
26. Borg JP, Ooi J, Levy E, Margolis B. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cell Biol. 1996;16:6229–6241. [PMC free article] [PubMed]
27. Morris SM, Cooper JA. Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic. 2001;2:111–123. [PubMed]
28. Wang B, Hu Q, Hearn MG, Shimizu K, Ware CB, Liggitt DH, Jin LW, Cool BH, Storm DR, Martin GM. Isoform-specific knockout of FE65 leads to impaired learning and memory. J Neurosci Res. 2004;75:12–24. [PubMed]
29. Lee J, Retamal C, Cuitino L, Caruano-Yzermans A, Shin JE, van Kerkhof P, Marzolo MP, Bu G. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes. J Biol Chem. 2008;283:11501–11508. [PMC free article] [PubMed]
30. Ho A, Liu X, Sudhof TC. Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2008;28:14392–14400. [PMC free article] [PubMed]
31. Cam JA, Zerbinatti CV, Knisely JM, Hecimovic S, Li Y, Bu G. The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. J Biol Chem. 2004;279:29639–29646. [PubMed]
32. Cam JA, Zerbinatti CV, Li Y, Bu G. Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein. J Biol Chem. 2005;280:15464–15470. [PubMed]
33. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005;102:13461–13466. [PMC free article] [PubMed]
34. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A. 1990;87:1561–1565. [PMC free article] [PubMed]
35. Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer’s disease beta-secretase. J Biol Chem. 2000;275:33729–33737. [PubMed]
36. Walter J, Fluhrer R, Hartung B, Willem M, Kaether C, Capell A, Lammich S, Multhaup G, Haass C. Phosphorylation regulates intracellular trafficking of beta-secretase. J Biol Chem. 2001;276:14634–14641. [PubMed]
37. Pastorino L, Ikin AF, Nairn AC, Pursnani A, Buxbaum JD. The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta) Mol Cell Neurosci. 2002;19:175–185. [PubMed]
38. Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994;269:17386–17389. [PubMed]
39. Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008;58:42–51. [PMC free article] [PubMed]
40. Thinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS. Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus. J Biol Chem. 1996;271:9390–9397. [PubMed]
41. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–390. [PubMed]
42. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518–522. [PubMed]
43. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398:513–517. [PubMed]
44. Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem. 2004;279:44945–44954. [PMC free article] [PubMed]
45. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Current Opinion in Lipidology. 2001;12:105–112. [PubMed]
46. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res. 2004;45:1375–1397. [PubMed]
47. Paratcha G, Ib·Òez CF. Lipid rafts and the control of neurotrophic factor signaling in the nervous system: variations on a theme. Current Opinion in Neurobiology. 2002;12:542–549. [PubMed]
48. Golub T, Wacha S, Caroni P. Spatial and temporal control of signaling through lipid rafts. Current Opinion in Neurobiology. 2004;14:542–550. [PubMed]
49. Kamiguchi H. The region-specific activities of lipid rafts during axon growth and guidance. Journal of Neurochemistry. 2006;98:330–335. [PubMed]
50. Kuo YM, Emmerling MR, Bisgaier CL, Essenburg AD, Lampert HC, Drumm D, Roher AE. Elevated low-density lipoprotein in Alzheimer’s disease correlates with brain abeta 1–42 levels. Biochem Biophys Res Commun. 1998;252:711–715. [PubMed]
51. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. Bmj. 2001;322:1447–1451. [PMC free article] [PubMed]
52. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356:1627–1631. [PubMed]
53. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439–1443. [PubMed]
54. Sparks DL, Scheff SW, Hunsaker JC, 3rd, Liu H, Landers T, Gross DR. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol. 1994;126:88–94. [PubMed]
55. Miida T, Takahashi A, Tanabe N, Ikeuchi T. Can statin therapy really reduce the risk of Alzheimer’s disease and slow its progression? Curr Opin Lipidol. 2005;16:619–623. [PubMed]
56. Canevari L, Clark JB. Alzheimer’s disease and cholesterol: the fat connection. Neurochem Res. 2007;32:739–750. [PubMed]
57. Hoyer S, Riederer P. Alzheimer disease-no target for statin treatment. A mini review. Neurochem Res. 2007;32:695–706. [PubMed]
58. Xiu J, Nordberg A, Shan KR, Yu WF, Olsson JM, Nordman T, Mousavi M, Guan ZZ. Lovastatin stimulates up-regulation of alpha7 nicotinic receptors in cultured neurons without cholesterol dependency, a mechanism involving production of the alpha-form of secreted amyloid precursor protein. J Neurosci Res. 2005;82:531–541. [PubMed]
59. Won JS, Im YB, Khan M, Contreras M, Singh AK, Singh I. Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts. J Neurochem. 2008;105:1536–1549. [PMC free article] [PubMed]
60. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998;95:6460–6464. [PMC free article] [PubMed]
61. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001;98:5856–5861. [PMC free article] [PubMed]
62. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;7:321–331. [PubMed]
63. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas-Bryant T, Tint GS, Wang R, Mercken M, Petanceska SS, Duff KE. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis. 2001;8:890–899. [PubMed]
64. Hartmann T. Role of amyloid precursor protein, amyloid-beta and gamma-secretase in cholesterol maintenance. Neurodegener Dis. 2006;3:305–311. [PubMed]
65. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2008;16:535–541. [PubMed]
66. Katsuno M, Adachi H, Sobue G. Getting a handle on Huntington’s disease: the case for cholesterol. Nat Med. 2009;15:253–254. [PubMed]
67. Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T. Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci. 2002;22:1679–1689. [PubMed]
68. Sun Y, Yao J, Kim TW, Tall AR. Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion. J Biol Chem. 2003;278:27688–27694. [PubMed]
69. Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol. 2001;3:905–912. [PubMed]
70. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem. 2005;280:18755–18770. [PubMed]
71. Sawamura N, Ko M, Yu W, Zou K, Hanada K, Suzuki T, Gong JS, Yanagisawa K, Michikawa M. Modulation of amyloid precursor protein cleavage by cellular sphingolipids. J Biol Chem. 2004;279:11984–11991. [PubMed]
72. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31–39. [PubMed]
73. Hancock JF. Lipid rafts: contentious only from simplistic standpoints. Nat Rev Mol Cell Biol. 2006;7:456–462. [PMC free article] [PubMed]
74. Helms JB, Zurzolo C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic. 2004;5:247–254. [PubMed]
75. Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol. 1998;14:111–136. [PubMed]
76. Lichtenberg D, Goni FM, Heerklotz H. Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem Sci. 2005;30:430–436. [PubMed]
77. Pike LJ. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J Lipid Res. 2006;47:1597–1598. [PubMed]
78. Brugger B, Sandhoff R, Wegehingel S, Gorgas K, Malsam J, Helms JB, Lehmann WD, Nickel W, Wieland FT. Evidence for segregation of sphingomyelin and cholesterol during formation of COPI-coated vesicles. J Cell Biol. 2000;151:507–518. [PMC free article] [PubMed]
79. Mukherjee S, Maxfield FR. Role of membrane organization and membrane domains in endocytic lipid trafficking. Traffic. 2000;1:203–211. [PubMed]
80. Puri V, Watanabe R, Dominguez M, Sun X, Wheatley CL, Marks DL, Pagano RE. Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nat Cell Biol. 1999;1:386–388. [PubMed]
81. Riddell DR, Christie G, Hussain I, Dingwall C. Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol. 2001;11:1288–1293. [PubMed]
82. Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS, Thinakaran G. Spatial segregation of g-secretase and substrates in distinct membrane domains. J Biol Chem. 2005;280:25892–25900. [PMC free article] [PubMed]
83. Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2003;100:11735–11740. [PMC free article] [PubMed]
84. Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003;160:113–123. [PMC free article] [PubMed]
85. Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, Dingwall C, De Strooper B, Dotti CG. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biol. 2004;167:953–960. [PMC free article] [PubMed]
86. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc Natl Acad Sci U S A. 2001;98:5815–5820. [PMC free article] [PubMed]
87. Hansen GH, Niels-Christiansen LL, Thorsen E, Immerdal L, Danielsen EM. Cholesterol depletion of enterocytes. Effect on the Golgi complex and apical membrane trafficking. J Biol Chem. 2000;275:5136–5142. [PubMed]
88. Hao M, Mukherjee S, Sun Y, Maxfield FR. Effects of cholesterol depletion and increased lipid unsaturation on the properties of endocytic membranes. J Biol Chem. 2004;279:14171–14178. [PubMed]
89. Kirsch C, Eckert GP, Mueller WE. Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol. 2003;65:843–856. [PubMed]
90. Melkonian KA, Ostermeyer AG, Chen JZ, Roth MG, Brown DA. Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated. J Biol Chem. 1999;274:3910–3917. [PubMed]
91. Benjannet S, Elagoz A, Wickham L, Mamarbachi M, Munzer JS, Basak A, Lazure C, Cromlish JA, Sisodia S, Checler F, Chretien M, Seidah NG. Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production. J Biol Chem. 2001;276:10879–10887. [PubMed]
92. Vetrivel KS, Meckler X, Chen Y, Nguyen PD, Seidah NG, Vassar R, Wong PC, Fukata M, Kounnas MZ, Thinakaran G. Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. J Biol Chem. 2009;284:3793–3803. [PMC free article] [PubMed]
93. Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE. Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis. 2002;9:11–23. [PubMed]
94. Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen P, Iwatsubo T, Tomita T, Wong PC, Green WN, Kounnas MZ, Thinakaran G. S-palmitoylation of gamma-secretase subunits nicastrin and APH-1. J Biol Chem. 2009;284:1373–1384. [PMC free article] [PubMed]
95. Scheiffele P, Roth MG, Simons K. Interaction of influenza virus haemagglutinin with sphingolipid-cholesterol membrane domains via its transmembrane domain. Embo J. 1997;16:5501–5508. [PMC free article] [PubMed]
96. Bruckner K, Pablo Labrador J, Scheiffele P, Herb A, Seeburg PH, Klein R. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron. 1999;22:511–524. [PubMed]
97. Yoon IS, Chen E, Busse T, Repetto E, Lakshmana MK, Koo EH, Kang DE. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB J. 2007;21:2742–2752. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...