Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques in the brain consisting of an aggregated form of amyloid β-peptide (Aβ) derived from sequential amyloidogenic processing of the amyloid precursor protein (APP) by membrane-bound proteases β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. The initial processing of APP by BACE1 is re-gulated by intracellular sorting events of the enzyme, which is a prime target for therapeutic intervention. GWAS (genome-wide sequencing studies) have identified several AD-susceptibility genes that are associated with the regulation of membrane trafficking, and substantial evidence now indicates that AD is likely to arise from defective membrane trafficking in either or both of the secretory and endocytic pathways. Considerable progress has been made in defining the intracellular trafficking pathways of BACE1 and APP and the sorting signals of these membrane proteins that define their itineraries. In this review we highlight recent advances in understanding the regulation of the intracellular sorting of BACE1 and APP, discuss how dysregulation of these trafficking events may lead to enhanced generation of the neurotoxic Aβ products in AD and highlight the unresolved questions in the field.

INTRODUCTION

The majority of the endocytosis pathways converge at the early endosomes where cargo is sorted for transport into the degradative pathway or recycling pathways. The early endosome is a highly dynamic organelle that is located in the periphery of the cell [1] and is the first endocytic compartment where internalized cargo from the plasma membrane (PM) is transported. Cargoes then undergo endosomal sorting from the early endosomes to various other compartments including the late endosome, recycling endosome and trans-Golgi network (TGN). Therefore the early endosome is a major sorting hub for endocytosed proteins, whereas the TGN is the major sorting hub of the secretory pathway. The analysis of the trafficking of individual cargo has been influential in defining the identity of endosomal sorting routes as well as the sorting signals and machinery components mediating these pathways. The pathogenesis of Alzheimer's disease (AD) has recently been linked to perturbations in the endosomal sorting and intracellular trafficking pathways for two key membrane cargo proteins, amyloid precursor protein (APP) and the β-secretase β-site APP-cleaving enzyme 1 (BACE1) which are responsible for the initial step in amyloid production. Thus the appreciation of the endosomal events associated with the trafficking of these two proteins, as well as the anterograde transport pathways from the endoplasmic reticulum (ER) to the cell surface, is paramount for the development of therapeutics to treat AD. Significant advances have been made in understanding the molecular basis for the regulation of post-Golgi trafficking and endosomal sorting in general [24] which provides a framework for predicting the impact of susceptible alleles on APP processing. We are also beginning to understand the transport pathways that could be relevant for APP processing in neurons. However, there remain significant gaps in our knowledge in this field. This is particularly true for neurons which have a very complex endosomal network and set of transport pathways. In this review we outline the pathological features of AD, the biochemistry of the pathways leading to amyloid production and the factors which are likely to be important in the regulation of the trafficking pathways of APP and BACE1, and highlight the areas that need further research.

ALZHEIMER'S DISEASE

AD is a chronic progressive age-related neurodegenerative disease and is one of the most prevalent forms of dementia. The disease can be further categorized based on the age of onset; the more common sporadic form, also called the late-onset form, and the early-onset/familial form of the disease. Although AD can be divided into different types based on age of onset and genetic predisposition, both forms of AD result in similar hallmark pathological characteristics which include (1) extensive neuronal atrophy (2), the appearance of extracellular deposition of senile amyloid neuritic plaques, and (3) intracellular neurofibrillary tangles. All of these features may be present to lesser extent in brains of elderly non-demented people. The dominant component of amyloid plaques is the amyloid β-peptide (Aβ) which is derived from the large APP precursor in a process called APP processing. The amyloid cascade hypothesis was proposed in 1992 by John Hardy and Gerald Higgins [5] where they proposed that the deposition and aggregation of Aβ to form senile plaques is the causative agent inducing all of the subsequent pathologies, including the formation of intracellular neurofibrillary tangles which would eventually lead to neuronal cell death and clinical dementia. The hypothesis was further supported by the discovery of mutations in APP and the presenilin proteins of the γ-secretase complex responsible for the early-onset familial disease causing full pathological features [6]. It was found that Aβ fibrils injected into the brains of mice are able to promote the phosphorylation of tau, leading to increased intracellular neurofibrillary tangles under experimental conditions [7]. Mutations in tau leading to the formation of intracellular neurofibrillary tangles can lead to frontotemporal disorders in other neurodegenerative diseases, but not the replication of the neurological features of AD. Intracellular neurofibrillary tangles are likely to be deposited subsequently to the increase in Aβ formation and the initial formation of plaques [8].

Late-onset sporadic form of AD

Late-onset AD accounts for the majority of cases (95%) of AD and begins after the age of 65 years [9]. It has been proposed that both genetic and environmental risk factors may contribute to this particular form of AD [9]. As the risk of AD doubles every 5 years after the age of 65, age remains the strongest non-genetic risk factor of AD [10]. mRNA transcript mutations and oxidative damage during aging are probably contributing factors [11,12]. Other non-genetic risk factors which have been reported include high-calorie and high-fat diets, diabetes mellitus and atherosclerosis [1315].

A large percentage of sporadic cases appear to be caused by polymorphic alleles that predispose an individual to increased susceptibility to AD. Whereas the mutations associated with familial early onset of disease are found in the genes encoding APP and presenilin proteins [6], the susceptibility alleles associated with sporadic cases affect a variety of cellular pathways. The APOE gene is one of the best documented susceptibility genes investigated in the development of AD. Human apolipoprotein (Apo) E is a major lipoprotein responsible in cholesterol homoeostasis. Although the frequency of the APOE allele in the predeposition of AD is well established, the role of ApoE in the pathogenesis of the disease is unclear [16]. Genome-wide sequencing studies (GWAS) have identified several other genes associated with AD and these genes include components of membrane trafficking. Interestingly, as the GWAS data has increased, trafficking machinery components have emerged as major risk factors in sporadic AD. These components include PICALM (phosphatidylinositol-binding clathrin assembly protein) and BIN1 (bridging integrator 1) [1721], which encode proteins directly involved in clathrin-dependent endocytosis [22]. Microarray studies in conjunction with GWAS have detected either changes in gene expression and/or multiple single nucleotide polymorphisms (SNPs) near or in genes that encode sorting nexin 3 (SNX3), Rab7, vacuolar protein sorting 35 (Vps35), Vps26, Rab5, Rab4 and SorLA [2329]. Interestingly, all of these genes encode trafficking machinery components that regulate transport of proteins from early endosomes, suggesting the critical importance of the early endosome in AD. Immunofluorescence and morphometric approaches have shown that altered endocytosis and endosome dysfunction is one of the earliest known neuropathology changes in AD, once again highlighting the relationship between defects in membrane trafficking and Aβ production [3032]. The reader is also directed to recent reviews on the specific topic of dysfunctional transport underlying the pathogenesis of this neurodegenerative disease [3335].

Amyloid precursor protein family of proteins

APP belongs to a broader family of type 1 transmembrane proteins which includes the APP homologues APLP-1 (amyloid precursor-like protein-1) [36] and APLP-2 [37]. These APP-like proteins have also been identified in Drosophilia melanogaster (APPL) [38], Caenorhabditis elegans (APL-1) [39] and zebrafish (APPa and APPb) [40] (reviewed in [41]). Both APLP-1 and APLP-2 proteins exhibit high levels of homology to APP as well as to each other and contain similar domain organization in their structures. However, the absence of the Aβ domain in APLP-1 and APLP-2 indicates that only APP can give rise to Aβ which forms the characteristic amyloid plaques in AD. The overall conservation of the amino acid sequence and expression patterns of APP, APLP-1 and APLP-2 in neuronal cells suggests that these proteins share similar physiological roles.

APP has been implicated in a number of neuronal processes. These include neuronal differentiation [42], migration [43], neurite outgrowth [42,44] and synapse formation [45]. Transgenic mice with single knockouts of APP [46], APLP-1 [47] or APLP-2 [48] presented no severe phenotypes, indicating that there is some functional redundancy among these proteins. In contrast, APP−/−/APLP-2−/− double knockouts and APLP-1−/−/APLP-2−/− double knockouts each showed lethal phenotype, whereas the APP−/−/APLP-1−/− mice remain viable [47]. Thus, there is genetic evidence that APP and APLP-1 have non-overlapping functions during early development, whereas APLP-2 shares some essential functions with APP and APLP-1 to explain the outcome, either lethal or viable, of the different double-knockout mice. Cognitive studies have also indicated that APP and APLP-2 are essential for the spatial learning in mice in addition to their roles in neuronal processes and development [49].

The gene encoding APP is located on chromosome 21 in humans [50]. Alternative splicing of the APP gene results in three major isoforms, APP695, APP751 and APP770 (695, 751 and 770 amino acids respectively). APP751 and APP770 are constitutively expressed in most tissues and contain a 56-amino-acid Kunitz protease inhibitor (KPI) domain within the luminal domain. APP695 is predominantly expressed in neurons and lacks the KPI domain [51,52].

β-Secretase family of proteins

The β-secretase BACE1 is responsible for the initial step in Aβ production. BACE1 is a type-I transmembrane aspartyl protease with a 21-residue N-terminal prodomain, a large 434-residue luminal domain, a transmembrane domain of 21 residues and a 24-residue cytoplasmic tail [53]. BACE1 is synthesized as a precursor protein, which is post-translationally modified by glycosylation [54] and phosphorylation, and is cleaved by a furin-like endo protease to produce a 75 kDa mature BACE1 [55]. Glycosylation of BACE1 appears to be important for the maximal activity of the enzyme, as mutations of the glycosylation sites drastically reduce proteolytic activity [56].

BACE1 has a protease active site within its luminal domain with aspartic acid residues within the two motifs, DTGS (residues 93–96) and DSGT (residues 289–292). Like other aspartyl proteases, BACE1 requires an acidic environment for optimal activity and studies overexpressing BACE1 have shown that it is mainly localized to intracellular compartments such as the Golgi, TGN and endosomes [5759]. Soluble BACE1 is unable to cleave APP efficiently, thus indicating that BACE1 needs to be membrane-bound and in close proximity to APP in order for cleavage to occur [60]. Therefore, the spatial distribution of both APP and BACE1 within the membranes and intracellular compartments of the cell has to be considered for processing. The specificity of BACE1 is fairly loose requiring a hydrophobic residue (preferably leucine) at position P1, polar or acidic residues at P2′ and P1, and bulky hydrophobic residues at P3 [61,62]. The preference for leucine at P1 by BACE1 is reflected by the enhanced cleavage of a mutant form of APP (known as the Swedish mutation) which is associated with early-onset disease [63]. The P1 hydrophobic residue methionine of the wild-type APP is replaced by leucine in APP of the Swedish mutation.

There are two BACE genes (BACE1 and BACE2) which share 64% amino acid homology; BACE2 is also a β-secretase [64]. BACE2 cleaves APP more efficiently at a different site which precludes Aβ production [65]. This suggests that cleavage of APP by BACE2 could limit Aβ production. Although BACE2 does not have a known consensus recognition site, the recent observation that BACE2, but not BACE1, selectively processes melanocyte protein (PMEL) indicates a difference in the substrate specificities of the two enzymes [66]. BACE1 has been found to be highly enriched in neurons but at lesser levels in surrounding astrocytes. On the other hand, BACE2 is expressed at very low levels in the brain with higher levels in peripheral tissues such as the pancreas, placenta and stomach [67]. This expression pattern may explain the tissue-specific basis of AD as a neurological disease.

BACE1 is considered the major β-secretase responsible for amyloidogenesis in the brain. BACE1−/− mice have greatly reduced levels of Aβ indicating that BACE1 is a key protein in the pathway responsible for the liberation of Aβ. BACE1-knockout mice show defects in synaptic function and plasticity and behavioural problems [68,69]. BACE1-knockout mice also showed myelination defects in the peripheral nervous system, probably from the lack of cleavage of another substrate, neuregulin [70]. These findings suggest that BACE1 cleavage of a number of proteins is required for normal physiological pathways, and a deficiency in BACE1 cleavage leads to dysfunction of multiple processes. In addition to APP, BACE1 substrates identified to date include APLP-1, APLP-2 [71,72], cell adhesion protein P-selectin glycoprotein ligand-1 [73], interleukin-1 receptor type II [74], α-2,6-sialyltransferase [75], low-density lipoprotein receptor-related protein [76], the β2 subunit of voltage-gated sodium channel [77,78], neuregulin-1 (NRG1), neuregulin-3 (NRG3) [79,80] and the neural cell adhesion molecules L1 and CHL1 [81]; and all of these substrates are membrane-bound. Proteome-wide unbiased approaches have identified numerous additional novel substrates [82,83] which include >20 substrates in neurons [82]. Therefore therapeutic approaches to inhibit BACE1 to reduce Aβ production pose significant problems associated with side effects from the interference of the processing of these additional substrates.

APP PROCESSING

APP is synthesized in the ER and transported through the Golgi to the TGN where APP undergoes major post-translational modifications including glycosylation, phosphorylation and sulfation [84]. From the TGN, APP is directed to the PM, probably via the early endosomes (discussed below). APP can be processed via two pathways, the non-amyloidogenic and the amyloidogenic pathway, where sequential proteolytic cleavage by three proteases termed α-, β- and γ-secretases determines the pathway taken (Figure 1) [85]. It is thought that, whereas the non-amyloidogenic processing of APP occurs predominantly on the PM due to a high abundance of α-secretase [86], amyloidogenic processing of APP is likely to occur intracellularly [87].

APP processing

Figure 1
APP processing

Illustrated are the two pathways of APP processing–the amyloidogenic pathway and the non-amyloidogenic pathway. In the amyloidogenic pathway, BACE1, a β-secretase, cleaves at the interface of the Aβ domain and the luminal domain to release the sAPPβ fragment and generate a 99-residue membrane-bound C-terminal fragment (β-CTF/C99) which is subsequently cleaved by γ-secretase to release Aβ. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain to release the sAPPα fragment, and generate a 83-residue membrane-bound C-terminal fragment (α-CTF/C83) which is subsequently cleaved by γ-secretase to release the p3 peptide fragment.

Figure 1
APP processing

Illustrated are the two pathways of APP processing–the amyloidogenic pathway and the non-amyloidogenic pathway. In the amyloidogenic pathway, BACE1, a β-secretase, cleaves at the interface of the Aβ domain and the luminal domain to release the sAPPβ fragment and generate a 99-residue membrane-bound C-terminal fragment (β-CTF/C99) which is subsequently cleaved by γ-secretase to release Aβ. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain to release the sAPPα fragment, and generate a 83-residue membrane-bound C-terminal fragment (α-CTF/C83) which is subsequently cleaved by γ-secretase to release the p3 peptide fragment.

In the amyloidogenic pathway, BACE1 cleaves APP between Met596 and Asp597 of the APP695 isoform, resulting in the release of sAPPβ, a soluble luminal APP derivative that is eventually secreted [88,89] and a membrane-bound 99-residue C-terminal fragment called C99 or β-CTF (Figure 1). Subsequent cleavage of C99 by γ-secretase results in the liberation of intact Aβ [89]. As γ-secretase can cleave the C99 fragment at multiple sites, a variety of Aβ species of different lengths are produced. The Aβ40 and Aβ42 species, which are 40 and 42 residues respectively, are normally the most abundant species (Figure 2) [90,91]. The Aβ42 variant represents approximately 10% of the total population of Aβ species and is more hydrophobic, more prone to fibril formation and considered the predominant form found in senile plaques [92]. As Aβ40 and Aβ42 products accumulate in the extracellular space, the Aβ42/Aβ40 ratio can be considered as a useful biomarker of AD [93,94]. Mass spectrometric analysis of the APP products derived from the cleavage by BACE1 revealed an additional cleavage site at Glu +11, producing a smaller membrane-bound C-terminal C89 fragment (Figure 2) [95,96], which is subsequently cleaved by γ-secretase to generate a truncated Aβ11–40/42 species. The prevalence of cleavage at this point has not been determined, but a mutation in this position has conferred a higher risk for AD and increases the production of the Aβ40 species [95,96].

Aβ fragments derived from APP processing

Figure 2
Aβ fragments derived from APP processing

APP contains three major domains, a large luminal N-terminal domain, a single transmembrane domain (also called the Aβ domain) and a shorter C-terminal cytoplasmic tail. Approximately half of the Aβ sequence lies intraluminally, with the rest of the domain contained within the phospholipid bilayer. Arrows indicate the cleavage sites of α-secretase (yellow), β-secretase (BACE1) (purple) and γ-secretase (green). The sequences of the different Aβ fragments arising from APP processing by BACE1 and g-secretase are shown below.

Figure 2
Aβ fragments derived from APP processing

APP contains three major domains, a large luminal N-terminal domain, a single transmembrane domain (also called the Aβ domain) and a shorter C-terminal cytoplasmic tail. Approximately half of the Aβ sequence lies intraluminally, with the rest of the domain contained within the phospholipid bilayer. Arrows indicate the cleavage sites of α-secretase (yellow), β-secretase (BACE1) (purple) and γ-secretase (green). The sequences of the different Aβ fragments arising from APP processing by BACE1 and g-secretase are shown below.

In the non-amyloidogenic pathway, cleavage by α-secretase between Lys612 and Leu613 of the APP695 isoform precludes the generation of intact Aβ. This cleavage results in the release of a soluble product of APP called sAPPα and a shorter membrane-bound fragment C83 or α-CTF [86] (Figure 2). In comparison with Aβ which is neurotoxic, sAPPα is found to be neuroprotective [97,98]. sAPPα is involved in regulating neural stem cell proliferation and central nervous system (CNS) development [42,99]. Further processing of α-CTF by γ-secretase yields a series of shorter hydrophobic peptides including Aβ17–40 and Aβ17–42, which are collectively called the p3 fragments (Figures 1 and 2) [100].

γ-Secretase is a multi-subunit aspartyl protease protein complex consisting of presenilin 1 (PS1) or presenilin 2 (PS2) which forms the catalytic core of γ-secretase, and three accessory proteins: nicastrin, anterior pharynx-defective-1 (APH-1) and presenilin enhancer-2 (PEN-2); the complex can only function through the molecular interactions of all four components [101,102]. γ-Secretase acts by cleaving the C99 fragment (β-CTF) at the membrane/cytoplasm boundary which is then processed by successive release of tri- and tetra-peptides to produce Aβ42 and Aβ40 [103,104]. There is considerable heterogeneity in the γ-secretase complex. APH-1 has been found to exist in two isoforms: APH-1A, which can be further spliced into long and short forms, and APH-1B. Together with either PS1 or PS2, six different functional γ-secretase complexes have been identified, but little is known about the physiological functions of each of these complexes [105,106]. Recently, evidence has been presented that different γ-secretase complexes can produce characteristic Aβ profiles [107], indicating that there are differences in the substrate processing of the different γ-secretase complexes. Indeed, γ-secretase generates a range of Aβ species with different lengths (reviewed in [85]). Heterogeneity of the Aβ species is important as the individual Aβ species differ in their cell toxicity [108,109]. Although Aβ42 and Aβ40 are the major species produced, it is unclear whether different Aβ species are produced in different intracellular locations.

The localization of the γ-secretase complexes is also relevant to identifying the intracellular site of Aβ generation. γ-Secretase has been reported to localize to the ER [110], TGN [111] and the endosomes [112]. The assembly, maturation and trafficking of γ-secretase is a fertile field currently under investigation (see [33,113,114] for reviews). After partial assembly in the ER, the immature γ-secretase complex recycles between the ER and cis-Golgi, a process dependent on the interaction of the immature complex with the retrieval receptor Rer1p [115,116]. Fully assembled γ-secretase is transported through the Golgi to the PM where it can undergo endocytosis and be transported along the endolysosmal/lysosomal pathway [33,113,114]. There are conflicting reports on the intracellular sites where γ-secretase is active. Studies from cell lines suggest that γ-secretase is active in the Golgi/TGN, PM and endosomes [111,117,118]. In rat neurons, γ-secretase activity was detected predominantly in synapses and endosomes and some activity also associated with Golgi membranes [119]. A study using a GFP reporter for γ-secretase activity, namely C99–GFP, detected γ-secretase activity only following post-Golgi transport of C99–GFP to the PM [120]. However, given that APP cytoplasmic sequences divert the trafficking of APP and C99 to the endosomes from the TGN (see below) and the possibility that the two membrane cargo may reside in different membrane domains in the TGN, γ-secretase activity in the Golgi/TGN cannot be excluded from these experiments. Knockout of the PS1 core subunit of γ-secretase resulted in the accumulation of APP C99 in the ER and Golgi of fibroblasts from the PS1-knockout mice, demonstrating that the substrate for γ-secretase is present in the secretory pathway [121]. Given the assembly pathway of the mature complex, it is unlikely that there is active γ-secretase in the ER, whereas active complex in the Golgi is very likely to be based on the above discussion. Aβ detected the ER [122124] may be due to the generation of Aβ products in the late Golgi and the subsequent transport by the known retrograde transport pathways from the Golgi/TGN to the ER [4]. In summary, γ-secretase is likely to be active in multiple locations and it is possible that cleavage by γ-secretase in different compartments may yield different Aβ profiles. As different Aβ species have differing neurotoxicity [93,108], it will be important to better understand the relationship between the intracellular sites of processing and the Aβ species generated.

Secretion/release of Aβ from cells

APP can be processed at multiple intracellular locations to produce Aβ species which are secreted from the cell and which subsequently aggregate to form amyloid plaques. Many studies utilize the accumulation of Aβ in the culture supernatant as a measure of total cellular APP processing and Aβ production. However, little is known of how intracellular Aβ species are released from the cell.

Aβ produced in the early endocytic pathway could be released by various recycling routes, both fast and slow. However, it is unclear how efficient these pathways would be for the release of soluble peptides, as transport to the cell surface involves mainly tubular carriers with a high surface area/volume ratio. The majority of the soluble contents of early endosomes remains in the vaculaor compartment which then follows the endosome/lysosomal pathway [125]. Exosomes provide one potential pathway for secretion of Aβ generated in endosomal compartments [126]. Studies performed by Rajendran et al. [127] have found that Aβ produced in the early endosome is transported to multi vesicular bodies (MVBs) and packaged into exosomes for secretion. On the other hand Aβ generated in the secretory pathway could be released from the cell by inclusion into post-Golgi transport carriers which fuse with the cell surface. There are multiple transport pathways from the Golgi to the cell surface, which include both regulated and constitutive transport pathways. Indeed it has been demonstrated that Aβ can be packed into TGN-derived secretory granules in chromaffin cells [128]. Constitutive post-Golgi transport pathways include transit through the Rab11-positive recycling endosomes [129] and the pathway from the recycling endosome to the PM could also provide a route for Aβ secretion. It also has been proposed that Aβ can be transported to the PM for secretion via autophagosomes [130,131]; however, the mechanism remains unclear. Of note is that very few studies have addressed the fundamental question of how the Aβ produced in neurons is secreted. One study has shown that Aβ generated in the axons may be released from the pre-synaptic sites [132,133]. It is likely that Aβ produced in the soma/dendrites is also secreted and may represent the majority of the Aβ produced by neurons [134]. Further work is needed to assess whether there are multiple pathways for Aβ secretion by neurons and, if so, what is the relative contribution of the individual pathways to the total load of extracellular Aβ.

TRAFFICKING ITINERARIES OF BACE1 AND APP

Overview from studies using different cell types

The subcellular localization of APP and BACE1 and the partitioning within intracellular compartments are likely to be important in the regulation of Aβ production [87,135,136]. A number of intracellular locations of APP processing by BACE1 have been proposed over the last 20 years. The predominant view currently is that APP processing occurs mainly in the TGN and the endosomal compartments [122124]. However, the relative contributions of these locations to Aβ production remain unclear [137,138]. The level of Aβ production depends on the steady-state distribution of both APP and BACE1 coupled with their trafficking pathways. There is no consensus in the literature regarding the steady-state distribution of APP and BACE1 within the cell. Often the Golgi is considered the major site for one or both of these membrane cargoes; however, this conclusion is confounded by the lack of extensive sets of organelle markers in most of these experiments and also the use of transfection systems where the high level of newly synthesized protein may result in the accumulation of cargo in the secretory pathway.

Although both APP and BACE1 are found at the PM, α-secretase is also enriched at the PM, which competes with BACE1 to process APP. Given the high levels of α-secretase at the cell surface, it is highly likely that majority of APP processing at the PM is through the non-amyloidogenic pathway [86,139]. Rather APP processing via the amyloidogenic pathway is likely to occur predominantly in intracellular compartments.

The generation of Aβ in the endosomal compartments [122124] is consistent with the rapid internalization of APP and BACE1 from the PM by clathrin-mediated endocytosis [59,140] into acidic endosomal compartments where it is more favourable for BACE1 activity. Furthermore, Aβ production is reduced when the endocytosis signal of APP is removed or when endocytosis is inhibited by culturing cells under low-potassium conditions [123,140]. FRET analysis revealed that APP and BACE1 are closely localized at the PM and that this localization remains strong as both proteins are internalized into the early endosomes [141]. Indeed, there is general consensus that, under normal conditions, the early endosome is a major site of APP processing by BACE1 [127,141143]. From the early endosome, it is likely that BACE1 and APP take different transport routes. APP is trafficked to the late endosomes then lysosomes [141,142,144,145] or it can be recycled back to the PM [146]. One of the complications of many of these studies is that the detection systems do not recognize the cleaved membrane associated forms of APP. Studies from our laboratory using either full-length APP or a cleavage-resistant APP chimaeric protein containing the transmembrane domain and cytoplasmic tail of APP fused to a reporter molecule confirmed that the majority of APP is trafficked to late endosomes/lysosomes [145] (Figure 3). The intracellular trafficking itinerary of BACE1 has been defined only recently. Early studies proposed that BACE1 may traffic from the early endosomes to the TGN [147] or that internalized BACE1 trafficked from early endosomes to late endosomes and then the lysosomes for degradation [148]. However, more recent work by our laboratory has shown that BACE1 traffics to the recycling endosomes instead of the TGN [145]. Moreover, BACE1 is subsequently recycled to the PM from the recycling endosomes, thus BACE1 is likely to have a similar trafficking itinerary as the transferrin receptor [145] (Figure 3). Other groups have also confirmed these findings [149152]. Work in our laboratory has also shown that expression of a chimaeric BACE 1 containing the cytoplasmic tail of TGN38 (BACE1–TGN38), resulted in a redirection of BACE1 to the TGN [145]. As a result, Chinese-hamster ovary (CHO) cells expressing the chimaeric BACE1–TGN38 construct generated higher levels of Aβ which is probably due to an increased concentration of BACE1–TGN38 in the TGN together with newly synthesized APP; the TGN is a slightly acidic compartment that provides favourable conditions for BACE1 cleavage of APP. This finding suggests that the trafficking itinerary of BACE1 via the recycling endosomes acts to sequester BACE1 from APP and is protective against excessive Aβ production. Furthermore, these findings indicate the potential for the generation of Aβ in the TGN as a consequence of newly synthesized BACE1 and APP trafficking through the secretory pathway (Figure 4).

Endocytic trafficking pathways of BACE1 and APP

Figure 3
Endocytic trafficking pathways of BACE1 and APP

Any APP processing at the PM is probably mediated by α-secretase, due to enrichment of α-secretase on the cell surface. BACE1 and APP are probably internalized from different subdomains of the PM via clathrin-mediated endocytosis into the early endosomes. From the early endosomes, the intracellular trafficking itineraries of BACE1 (purple) and APP (yellow) diverge and APP is trafficked to the late endosome/lysosome for degradation whereas BACE1 is transported to the recycling endosomes before being recycling back to the cell surface. The normal trafficking of BACE1 and APP is likely to lead to low levels of APP processing due to the different intracellular trafficking routes of APP and BACE1. Rab11 has been shown to regulate BACE1 transport, and other machinery that could participate in BACE1 trafficking (shown in green) includes SNX3, SNX4, Rab22, vesicle-associated membrane protein 3 (Vamp3) and Arf6, Rab4.

Figure 3
Endocytic trafficking pathways of BACE1 and APP

Any APP processing at the PM is probably mediated by α-secretase, due to enrichment of α-secretase on the cell surface. BACE1 and APP are probably internalized from different subdomains of the PM via clathrin-mediated endocytosis into the early endosomes. From the early endosomes, the intracellular trafficking itineraries of BACE1 (purple) and APP (yellow) diverge and APP is trafficked to the late endosome/lysosome for degradation whereas BACE1 is transported to the recycling endosomes before being recycling back to the cell surface. The normal trafficking of BACE1 and APP is likely to lead to low levels of APP processing due to the different intracellular trafficking routes of APP and BACE1. Rab11 has been shown to regulate BACE1 transport, and other machinery that could participate in BACE1 trafficking (shown in green) includes SNX3, SNX4, Rab22, vesicle-associated membrane protein 3 (Vamp3) and Arf6, Rab4.

Anterograde transport of newly synthesized BACE1 and APP

Figure 4
Anterograde transport of newly synthesized BACE1 and APP

Both APP and BACE1 are synthesized as membrane proteins in the ER and subsequently are transported to the Golgi. At the TGN the two membrane cargoes follow distinct pathways to the plasma membrane, APP probably via early endosomes and BACE1 either directly to the PM or via recycling endosomes.

Figure 4
Anterograde transport of newly synthesized BACE1 and APP

Both APP and BACE1 are synthesized as membrane proteins in the ER and subsequently are transported to the Golgi. At the TGN the two membrane cargoes follow distinct pathways to the plasma membrane, APP probably via early endosomes and BACE1 either directly to the PM or via recycling endosomes.

Partitioning of cargo into distinct membrane microdomains of individual compartments is another important issue when considering the potential of APP and BACE1 to interact. A subset of both APP and BACE1 has also been found to localize to lipid rafts along with γ-secretase [153]. Increased cholesterol in the cell increases partitioning of both proteins and γ-secretase into the lipid rafts which in turn increases Aβ production, suggesting that lipid rafts can also provide an optimal environment for Aβ production [154156].

Trafficking of BACE1 and APP in neurons

A fundamental issue in understanding the regulation of Aβ production is how the observations on the trafficking of APP and BACE1 in non-neuronal cells relate to trafficking of these cargo in primary neurons. Only recently have studies begun to define the trafficking and recycling of APP and BACE1 in neuronal cells (Figure 5). Neurons are polarized cells with a complex endosomal network within the soma/cell body, dendrites and axon [157,158]. Recycling of membrane cargo can occur in both dendritic spines and axons. Membrane cargo is not restricted to one location of the neuron as bidirectional transport has been demonstrated in both dendrites and axons [159]. Also, as is the case for other polarized cells, transcytosis of cargo can occur between the two distinct domains, namely from dendrites to axons [160]. Distinct machinery is required to regulate these transport pathways and some of this machinery may be unique to neurons.

Trafficking pathways of APP and BACE1 in neurons

Figure 5
Trafficking pathways of APP and BACE1 in neurons

Shown are some of the proposed trafficking pathways where APP (yellow oval) and BACE1 (red triangle) converge in neurons. See the text for discussion and alternative possibilities.

Figure 5
Trafficking pathways of APP and BACE1 in neurons

Shown are some of the proposed trafficking pathways where APP (yellow oval) and BACE1 (red triangle) converge in neurons. See the text for discussion and alternative possibilities.

Early studies, based predominantly on the accumulation of Aβ in the secretory pathway, suggested that APP and BACE1 in neuronal cells are concentrated in the Golgi/TGN [161163] and these suggestions, based on indirect evidence, continue to dominate some of the current literature. However, given the lack of recycling endosome markers in these early studies, and the proximity of Rab11+recycling endosome endosomes to the Golgi/TGN, there remains some uncertainty about the precise intracellular location of the majority of Aβ. Moreover, the conclusion regarding the location of APP and BACE1 in these early studies was based on the site where the Aβ was detected rather than direct localization of endogenous APP and BACE1. The precise distribution of endogenous APP and BACE1 in primary neurons still remains poorly defined. Nonetheless these early studies did highlight the accumulation of Aβ in the secretory pathway and these findings need to be integrated into the current models.

More recent studies have demonstrated that endogenous APP and BACE1 are predominantly located in the somato/dendrites of neurons [134]. In addition, exogenously expressed BACE1 in neurons is associated predominantly with recycling endosomes as marked by transferrin receptor (TfR), whereas the majority of exogenous APP appeared to co-localize with a Golgi marker [149]. BACE1 has been shown to be transported in recycling endosomes within dendrites and axons of hippocampal neurons [152]. From an RNAi screen, Rab11 has been identified as a key regulator of BACE1 endosomal recycling and Aβ production in both non-neuronal cells and primary neurons [150], highlighting the importance of the recycling endosome compartment in the trafficking pathways underlying AD. Rab11 function has also been shown to be essential for sorting of BACE1 to axons and for presynaptic BACE1 localization [152]. By live imaging it has been shown that internalized BACE1 in dendrites undergo retrograde transport to the cell body, dependent on EHD regulatory proteins, whereas in axons BACE1 undergoes bidirectional transport [151]. There are differing reports on whether APP and BACE1 are transported together or in separate transport vesicles along axons [164,165]. Recently, Das et al. [164] have used an elegant approach based on fluorescence complementation to visualize APP–BACE1 interactions in neurons; interactions were detected in both biosynthetic and endocytic pathways including dendritic spines and axons. Therefore there is the potential for BACE1-mediated cleavage of APP at multiple sites in neurons; the contribution at these different sites needs to be quantified as does the sites of γ-secretase cleavage and the mechanism of Aβ secretion from the site of production. More information is also required on the transport pathways of newly synthesized APP and BACE1 in neurons and their precise itineraries.

Sorting motifs and molecular machinery involved in APP trafficking

As discussed, intracellular trafficking of proteins can be attributed to the interactions between sorting motifs on cargo with components of the molecular machinery. Interactions of cargo adaptors with sorting signals on the cytoplasmic domains of membrane proteins promote their sorting into nascent transport carriers. One family of adaptor proteins (namely AP1, AP2, AP3, AP4 and AP5) is important for transport pathways from the PM (e.g. AP2/clathrin-mediated endocytosis) and from the TGN and endosomes [166]. APP and BACE1 contain sorting motifs on their C-terminal cytoplasmic tails. APP has three tyrosine-based motifs in its cytoplasmic tail (Figure 6A). The YTSI and GYENPTY sequences of APP (Figure 6A) conform to the YXXϕ and NPXY consensus motifs respectively, where X represents any amino acid residue and ϕ represents a bulky hydrophobic residue. Tyrosine-based YXXϕ motifs have been shown to interact with the μ subunit of four AP complexes [167]. The μ2 subunit of AP2 exhibits the highest affinity for this particular motif [167]. However, although the YTSI motif found in APP conforms to the YXXϕ consensus sequence, binding studies have shown that this motif in APP does not interact with the μ2 subunit of AP2 [168]. Notably the serine residue (position 655 in APP695) in the YTSI motif has been observed to be phosphorylated in different cell lines as well as in rat brain homogenates [169]. Phosphorylation of this motif can affect the downstream trafficking from the early endosomes. Recent studies have shown that the mutation of the serine residue to an alanine residue (S655A), to mimic the dephosphorylated form, resulted in APP being targeted to the lysosome after internalization while mutating the serine residue to a glutamate residue (S655E), to mimic the phosphorylated form, targeted APP from the early endosomes to the TGN [170,171]. However, the effect of APP Ser655 phosphorylation on APP trafficking in neurons and the regulation of APP Ser655 phosphorylation in neurons remains to be investigated.

Sorting signals on cytoplasmic tails of APP and BACE1

Figure 6
Sorting signals on cytoplasmic tails of APP and BACE1

Sorting of BACE1 and APP is regulated by the sorting signals on their cytoplasmic tails. (A) Internalization of APP is mediated by the GYENPTY motif. The novel YKFFE motif has recently been found to interact with the adaptor AP4, an interaction required for post-Golgi trafficking of APP. Phosphorylation of the YTSI motif have shown to increase retrograde transport of APP from the early endosome (see the text). (B) Internalization of BACE1 from the PM is mediated by the DDISLL motif which interacts directly with AP2. GGA proteins has been shown to interact with the DISLL motif which may regulate endosomal trafficking. The lysine residue at the C-terminus can be ubiquitinated to promote increased trafficking from the early endosome to the late endosomes/lysosomes.

Figure 6
Sorting signals on cytoplasmic tails of APP and BACE1

Sorting of BACE1 and APP is regulated by the sorting signals on their cytoplasmic tails. (A) Internalization of APP is mediated by the GYENPTY motif. The novel YKFFE motif has recently been found to interact with the adaptor AP4, an interaction required for post-Golgi trafficking of APP. Phosphorylation of the YTSI motif have shown to increase retrograde transport of APP from the early endosome (see the text). (B) Internalization of BACE1 from the PM is mediated by the DDISLL motif which interacts directly with AP2. GGA proteins has been shown to interact with the DISLL motif which may regulate endosomal trafficking. The lysine residue at the C-terminus can be ubiquitinated to promote increased trafficking from the early endosome to the late endosomes/lysosomes.

The internalization of APP from the PM is thought to be dependent on an extension of the classical NPXY motif, namely a GYENPTY motif [173] (Figure 6A). This motif is conserved in all forms of APP from different organisms which signifies the importance of this motif for the function of APP [172]. NPXY sorting motifs can mediate internalization through the recruitment of the AP2 complex for clathrin-mediated endocytosis [167]. Residues flanking the NPXY motif can enhance recognition of the motif by AP2 and increase the efficiency of internalization. Mutations of the glycine and the first tyrosine residue of the GYENPTY motif of APP have been shown to be critical for its internalization [140,173]. These mutations result in reduced endocytosis and Aβ production [174].

Proteins containing a phospho-tyrosine binding (PTB) domain can also interact with NPXY motifs. APP endocytosis has been shown to be also dependent on Disabled-2 (Dab2) which is a PTB domain-containing protein and via the interaction with the GYENPTY sorting motif [175]. The Mint/X11 family of adaptor proteins has also been shown to interact with the GYENPTY motif on APP [176,177]. This family comprises Mint1/X11a, Mint2/X11b and Mint3/X11c where Mint1 and Mint2 are expressed predominantly in the brain, whereas Mint3 is ubiquitously expressed [176]. Mint adaptors all share a highly conserved C-terminal PTB domain and two PDZ domains and the PTB domain is able to bind to the GYENPTY motif of APP [177]. Mint1 has been shown to regulate both secretory and endocytic trafficking of APP which affects its processing [178]. Mint2 can be phosphorylated by Src kinase which in turn accelerates APP endocytosis and increases APP sorting to autophagosomes [179]. Conversely, a phospho-resistant form of Mint2 increases recycling of internalized APP back to the PM with increased Aβ production [179]. Mint3 localizes to the TGN [180] and has been shown to regulate the APP trafficking from the TGN to the PM [181,182]. In addition, SNX17 can also bind to APP via the GYENPTY motif and has been reported to be involved in the recycling of APP from the early endosomes to the PM. Depletion of SNX17 results in a decrease in steady-state levels of APP with an increase in Aβ production [175]. Together these results demonstrate that the GYENPTY sorting motif of APP interacts with a number of adaptors which mediate a number of different transport pathways.

The third tyrosine-containing motif (YKFFE) of APP (Figure 6A) has been characterized and was proposed to mediate TGN to endosome transport of APP [168]. The motif was found to interact with the μ4 subunit of AP4. Although the YKFFE motif may conform to the YXXϕ motif, structural and binding studies revealed that the interaction of μ4 with YKFFE differs from the interaction of the μ2 subunit with consensus YXXϕ motifs [168]. Mutation of the YKFFE motif shifts APP localization from the endosomes to the TGN and also increased Aβ generation [168]. This clearly suggests that the transport of APP out of the TGN is critical to protect against excessive Aβ production. Hence the proposal, yet to be directly demonstrated, that post-Golgi transport of newly synthesized APP to the endosomes would divert APP from the major anterograde transport pathways to the PM. In contrast newly synthesized BACE1 is likely to be transported by these latter pathways (Figure 4).

Sorting motifs and molecular machinery involved in BACE1 trafficking

BACE1 contains an acidic/cluster dileucine motif (DISLL) in its cytoplasmic tail (Figure 6B) and is a critical recognition signal for BACE1 endocytosis [59,183] as well as trafficking of BACE1 intracellularly [148,184187]. Mutation of the dileucine residues in the motif to alanine residues resulted in a decrease in internalization of BACE1 [59,183], indicating that the motif is essential for endocytosis. More recently, this DISLL sequence has been shown to be embedded within a longer [DE]XXXL[LI]-motif sequence, namely DDISLL, where the first aspartate residue (Asp495) and the dileucine residues have been shown to be required for clathrin-dependent internalization of BACE1 from the PM [188]. Although our laboratory and other groups have shown that the dileucine residues [145] and Asp495 [188] are required for AP2-mediated clathrin-dependent endocytosis, another study proposed that BACE1 was internalized by a clathrin-independent ADP-ribosylation factor 6 (Arf6)-dependent endocytosis pathway [134]. This internalization pathway was suggested to be mediated by the interaction of Arf6 effectors with the DISLL motif. Arf6 is localized to the PM where it can regulate both clathrin-dependent and independent endocytosis. Arf6 is also located in endosomal compartments where it can mediate recycling of proteins from the recycling endosomes to the PM [189]. Further work performed by our laboratory showed that rapid internalization of BACE1 was not affected by RNAi depletion of Arf6 [145]. Extended periods of internalization for 60 min or longer resulted in similar levels of internalization BACE1 in both control or AP2- or Arf6-depleted cells, suggesting that bulk endocytosis may also contribute to the endocytosis of BACE1 [145].

In vitro binding studies have also showed that Golgi-localized γ-ear-containing Arf-binding (GGA) proteins can interact with the DISLL motif [147], an interaction which regulates intracellular transport. Initially, GGA adaptor proteins were demonstrated to mediate transport from the TGN to the endosomes [190]. More recently, there has been evidence that GGA proteins may also regulate endosomal sorting events [186,191]. Therefore, the BACE1–GGA protein interactions may be relevant for either anterograde or endosomal transport. Ser498 of the DISLL motif can be phosphorylated by protein kinase CKI and Ser498 phosphorylation enhances binding of GGA1 to BACE1 [187]. Mutagenesis of Ser498 to phospho-mimetic mutants altered the distribution of BACE1. Mutagenesis of Ser498 to an alanine to mimic a non-phosphorylated BACE1 resulted in the accumulation of BACE1 in the early endosomes [147,183,192]. In contrast, mutating Ser498 to an aspartate to mimic the phosphorylated BACE1 results in BACE1 transport from the early endosomes to a perinuclear compartment thought to be the TGN [147,183,192]. Depletion of GGA proteins by RNAi or disruption of phosphorylation of BACE1 on Ser498 resulted in the accumulation of BACE1 in early endosomes and enhanced Aβ generation [147,186], suggesting that the early endosomes may be a key compartment for APP processing to generate Aβ.

GGA proteins also have the ability to bind ubiquitinated proteins for the sorting to the lysosomes for degradation. BACE1 can be ubiquitinated on Lys501 in the cytoplasmic tail and is subsequently bound by GGA3 for targeting to the lysosomes, suggesting that ubiquitination of the cytoplasmic tail of BACE1 can serve as a sorting motif for delivery to the lysosomes [193]. This finding was supported by Tesco et al. [194] who showed that depletion of GGA3 caused an increased in the level of BACE1 as well as the Aβ level. Collectively, these findings strongly support that GGA proteins function not only for post-Golgi trafficking but also for sorting from the early endosomes to other endosomal compartments.

Collectively, post-translational modifications, particularly phosphorylation, are likely to be important in the regulation of the transport kinetics and the itinerary of these cargo. However, there is a scarcity of information on the impact of phosphorylation of APP and BACE1 on their trafficking in neurons. This is an important issue that needs to be explored as it may be critical to understand the regulation of APP processing.

The role of retromer in Alzheimer's disease

A role for the early endosome as a major site for Aβ processing was further reinforced with the discovery that components of the transport machinery complex retromer were found to be significantly down-regulated in brains of patients with AD. One of the retromer components, SNX6, has also been shown to interact with BACE1 [195]. Depletion of SNX6 perturbed the endocytic transport of BACE1, resulting in an accumulation of BACE1 in the early endosomes and increased Aβ production. Thus SNX6 may be involved in the endosomal sorting of BACE1 from the early endosomes.

Microarray analysis of AD and non-AD brains have revealed significant down-regulation of genes encoding Vps35 and Vps26, which are also components of the retromer complex, in patients with AD as compared with unaffected individuals [25]. Further studies using RNAi silencing of Vps35 in cultured cells resulted in increased Aβ generation [25,27], whereas overexpression of Vps35 diminished Aβ generation [25]. These findings support the proposal that dysregulation of components of the retromer complex results in the prolonged residence of APP and BACE1 in the early endosome and increased Aβ production. Subsequent animal studies have also re-emphasized the importance of retromer in the regulation of APP processing. Mice expressing reduced levels of retromer (Vps26+/−) were found to have elevated Aβ levels [196] and hippocampal dysfunction [26] and Vps35 haploinsufficiency in mice enhances AD pathology [197]. In a recent study, Mecozzi et al. [198] used small-molecular chaperones to stabilize Vps35 and Vps29 in the retromer complex, which protecting against thermal denaturation and proteolytic degradation. They showed that stabilization of the retromer complex in primary neurons increased APP traffic out of the early endosomes and reduced Aβ production [198]. Collectively the evidence shows that the early endosome is a crucial site for APP processing by BACE1 and that defects in retromer-mediated transport pathways out of the early endosome results in increased Aβ generation. These studies also demonstrated the potential of small-molecular chaperones as pharmacological agents to stabilize trafficking components and improve physiological function. For further details on the role of retromer in AD, the reader is directed to a number of reviews which summarize this topic [199201].

One complication here is that retromer is known to regulate at least three different endosomal export pathways, namely two retrograde transport pathways to the TGN and also a fast recycling pathway to the cell surface [202204]. In addition there is evidence that retromer is involved in a transport pathway from the early endosomes to the recycling endosomes [203,204]. Retromer is not a typical coat complex, but rather there are a number of different retromer complexes, all containing the Vps26–Vps29–Vps35 core trimer, and additional proteins which interact with retromer, such as sorting nexins, which contribute to cargo selection and membrane trafficking. Hence it is not surprising that knockouts of core retromer subunits is lethal in model organisms [197,205]. Reduced levels of Vps26 and Vps35 in AD patients and alterations in the levels of core retromer subunits in mouse models described above are likely to have an impact on multiple transport pathways and it is therefore difficult to distinguish direct effects on APP and BACE1 trafficking from indirect consequences arising from global endosomal dysfunction. Moreover, perturbation of retromer levels also influences the morphology of the Golgi [203,206,207], probably due to altered membrane flux into the TGN. Hence, the dysfunction of early endosomes could perturb Aβ production at both the early endosomes and the TGN. This is relevant to the molecular understanding of the role of retromer in AD and in the design of therapeutic strategies.

An important finding which gives insight into a molecular basis for a perturbation in endosomal sorting, is that the sorting protein-related receptor (SORL1) (also denoted as SorLA or LR11) was also found to be a candidate gene associated with late-onset AD [2729]. SorLA/LR11 is a member of the Vps10 family of proteins. The six-amino-acid FANSHY sequence on the cytoplasmic tail of SorLA has been identified to bind Vps26 of the retromer complex [208]. In the presence of SorLA overexpression, there was strong co-localization of APP and Vps35 [208]. In contrast, in cells expressing a non-interacting mutant of SorLA, there was little co-localization between APP and Vps35. Therefore it has been proposed that SorLA may act as a bridge for retromer-mediated sorting of APP [208]. Overexpression of SorLA reduced Aβ production, whereas depletion of SorLA expression in mice increased Aβ production [209]. Thus, SorLA is protective against increased Aβ production. Sortilin, another member of the Vps10 family of proteins has also been implicated as a regulator of BACE1 retrograde trafficking [210]. The cytoplasmic domain of sortilin is required for the intracellular sorting of BACE1 from early endosomes; overexpression of sortilin mutants with truncated cytoplasmic tails resulted in BACE1 accumulation in the early endosomes as retrograde transport is impaired [210]. As sortilin, like SorLA, is sorted by retromer-mediated transport, retromer may be involved in regulating the trafficking of APP and BACE1 indirectly via Vps10-containing proteins.

A conclusion from these studies is that perturbations of endosomal sorting and maturation influences Aβ production. It is unlikely that AD is associated with a complete block in a transport pathway as this would probably be lethal, as is the case for knockout of retromer components described above. It is more likely that there are subtle perturbations of the kinetics of transport arising from changes in levels of retromer core components or cargo receptors. Perturbation of the trafficking of BACE1 and/or APP, mediated by genetic factors and/or signalling events, could alter their residency time in overlapping compartments, which in turn could lead to enhanced levels of APP processing and Aβ generation. Figure 7 illustrates the consequence of alterations in the residency time of APP and BACE1 in early endosomes. As AD progresses very slowly, changes in kinetics of transport need only be relatively small to account for an increase in the Aβ level over a period of months and years. The same principle could apply to the transit of newly synthesized APP and BACE1 through the TGN. There is evidence that the Golgi is disrupted in AD [211,212], and altered kinetics of transport of APP and BACE1 out of the TGN could result in altered levels of APP processing. Hence alterations in temporal and spatial events of trafficking in either the early endosomes or TGN could lead to modifications in APP processing.

Model of altered APP and BACE1 trafficking resulting in enhanced Aβ production

Figure 7
Model of altered APP and BACE1 trafficking resulting in enhanced Aβ production

Shown is the example of altered transport kinetics of BACE1 and APP through the early endosome arising as a consequence of reduced levels of endosomal machinery such as retromer. (A) The trafficking itinerary and distribution of APP and BACE1 under physiological conditions. (B) Alterations in trafficking machinery, such as retromer, or modifications of post-translational modifications of APP or BACE1 could reduce the rate of transport through the early endosome. The consequence would be an alteration in the steady-state distribution of cargo throughout the endosomal system with a build up of BACE1 and/or APP in the early endosome resulting in enhanced APP processing and increased levels of Aβ. A similar situation may occur in the TGN following altered transport kinetics of these cargo.

Figure 7
Model of altered APP and BACE1 trafficking resulting in enhanced Aβ production

Shown is the example of altered transport kinetics of BACE1 and APP through the early endosome arising as a consequence of reduced levels of endosomal machinery such as retromer. (A) The trafficking itinerary and distribution of APP and BACE1 under physiological conditions. (B) Alterations in trafficking machinery, such as retromer, or modifications of post-translational modifications of APP or BACE1 could reduce the rate of transport through the early endosome. The consequence would be an alteration in the steady-state distribution of cargo throughout the endosomal system with a build up of BACE1 and/or APP in the early endosome resulting in enhanced APP processing and increased levels of Aβ. A similar situation may occur in the TGN following altered transport kinetics of these cargo.

Impact of neuronal stimulation on the trafficking of BACE1 and APP

There is emerging evidence indicating that Aβ production is linked to levels of neuronal activity in the brain [149,213215]. Increased neuronal activity results in increased Aβ production [213]. Interestingly, the regions of the brain that produces the most Aβ plaques are cortical regions of the brain which exhibit higher baseline metabolic activity than other parts of the brain [216218]. This increased metabolic activity is suggested to be linked to increased neuronal and synaptic activity.

Aβ production resulting from increased neuronal activity has been attributed to clathrin-dependent endocytosis of surface APP, endosomal processing of APP and Aβ release from the cells [136]. Using dynamin dominant-negative inhibitory peptides that were infused into the brains of mice, Cirrito et al. [136] reported that ∼70% of Aβ production in the brain arises from the endocytosis-associated mechanism, and a large fraction of the Aβ production depended on neuronal activity. A subsequent study conducted by Das et al. [149] revealed that ligand-induced activation of neurons results in increased Aβ production. Using tagged APP and BACE1 constructs, they demonstrated that there was enhanced co-localization of exogenously expressed APP and BACE1 following glycine-induced N-methyl-D-aspartate receptor (NMDAR) activation, potassium activation or γ-aminobutyric acid (GABA) antagonist picrotoxin treatment [149]. They further showed that APP is likely to be redirected to the recycling endosomes where BACE1 is residing during neuronal stimulation leading to enhanced Aβ production in the recycling endosomes. These findings demonstrate that the trafficking of APP and BACE1 could be altered under different physiological conditions. It will now be important to follow up these studies and determine the behaviour of endogenous BACE1 and APP in stimulated neurons and the mechanism for altered APP trafficking induced by cell signalling events.

Table 1
Unresolved issues which are relevant to understanding how dysregulation of intracellular transport of APP and BACE1 leads to enhanced levels of Aβ products
1. What are the anterograde transport pathways of newly synthesized APP and BACE1? 
2. What is the proportion of newly synthesized APP or BACE1 that traffics to the cell surface? 
3. What is the steady-state distribution of endogenous BACE1 and APP in neurons? Where is the majority of BACE1 and APP located? 
4. What is the impact of post-translational modifications on the kinetics of intracellular transport of APP and BACE1? 
5. What are the relative contributions of the endosomes and TGN in BACE1 cleavage of APP and Aβ production? And how do these locations affect the size and species of Aβ produced? 
6. What is the trafficking itinerary of γ-secretase? And what is the relative cellular distribution of the different γ-secretase isoforms in neurons? 
7. How is intracellular Aβ secreted from the cell? Are there multiple pathways? 
8. What is the precise organization of the TGN and endosomal system in neurons? Are there neuronal specific transport pathways between the TGN/endosomal network? 
9. What is the impact of membrane microdomains on the segregation of APP and BACE1 within a single compartment, for example the early endosomes and the TGN? 
1. What are the anterograde transport pathways of newly synthesized APP and BACE1? 
2. What is the proportion of newly synthesized APP or BACE1 that traffics to the cell surface? 
3. What is the steady-state distribution of endogenous BACE1 and APP in neurons? Where is the majority of BACE1 and APP located? 
4. What is the impact of post-translational modifications on the kinetics of intracellular transport of APP and BACE1? 
5. What are the relative contributions of the endosomes and TGN in BACE1 cleavage of APP and Aβ production? And how do these locations affect the size and species of Aβ produced? 
6. What is the trafficking itinerary of γ-secretase? And what is the relative cellular distribution of the different γ-secretase isoforms in neurons? 
7. How is intracellular Aβ secreted from the cell? Are there multiple pathways? 
8. What is the precise organization of the TGN and endosomal system in neurons? Are there neuronal specific transport pathways between the TGN/endosomal network? 
9. What is the impact of membrane microdomains on the segregation of APP and BACE1 within a single compartment, for example the early endosomes and the TGN? 

CONCLUSION AND FUTURE DIRECTIONS

In spite of the recent advances there remain considerable gaps in our knowledge on APP processing and Aβ secretion and the molecular basis leading to enhanced Aβ production in neurons and to AD. Box 1 summarizes important issues that need to be resolved in the field. As discussed in this review, it is clear that APP and BACE1 have overlapping but distinct pathways in both the anterograde and recycling transport pathways (Figures 3 and 4). It seems likely that the distinct trafficking pathways of APP and BACE1 provide the capacity to finely regulate the extent of co-localization and thereby regulate APP processing and Aβ production. The details of the trafficking of APP and BACE1 in neurons is now emerging; however, an impediment to further progress on defining the itinerary of APP and BACE1 in neurons is the limited knowledge of the organization of the secretory and endocytic pathways in this specialized cell type. In particular the organization of different endosomal compartments in the cell body, dendritic and axons, and the dynamic transport pathways emerging from these compartments are not well defined at the cell biological level. This is important as endosomal transport is central for neuronal polarized transport to establish and maintain the complex subdomains of dendrites and axons [219]. The identity of the endosomal machinery in neurons is also incomplete and is likely to include regulators which are specific for this cell type. The use of model cargos and endosomal markers coupled with high-resolution imaging techniques, including super-resolution microscopy, correlative light and electron microscopy, and EM tomography should generate a better map of the spatial relationship of the compartments and transport pathways in neurons. The cross-talk between the endocytic and secretory pathways is also critical [220], yet there is limited knowledge of these pathways in neurons. More detailed appreciation is required of the trafficking pathways between the TGN and the different populations of endosomes in neurons and their relevance to APP and BACE1 trafficking. Quantitative data are also required on the level of convergence of APP and BACE1 in the different intracellular compartments of neurons and how this convergence influences the production and identity of Aβ generated. The use of photoactivatable probes and new biosensors have considerable potential to monitor the movement and precise spatial relationship between APP and BACE1 in overlapping compartments in live cells and to identify the pathways for secretion of Aβ products.

A major advance has been the realization that disruption of endosomal machinery components results in increased Aβ production; it is now important to determine whether a similar scenario occurs in the TGN especially given the early papers demonstrating the importance of the secretory pathway in Aβ production. The generation of mouse lines genetically altered in regulators of TGN transport and post-Golgi trafficking would be of interest in assessing the contribution of the Golgi to APP processing and Aβ secretion, particularly in neurons.

External stimuli can induce changes to the trafficking itinerary of APP in primary neurons which could also affect Aβ production. Further studies need to explore the link between signalling and membrane trafficking events. To date the effect of signalling on the trafficking of exogenously expressed APP has been examined in neurons. There are a number of questions that now need to be addressed. How does endogenous APP behave under different signalling events? What is the altered trafficking due to? Understanding the cross-talk between membrane transport and signalling is a fundamental question not only for neuronal development and networking but also for cell regulation in general. Defining the events of APP and BACE1 trafficking in primary neurons is likely to uncover mechanism of general relevance in cell signalling.

In conclusion, knowledge of the membrane trafficking events of APP and BACE1 is critical for the biochemical pathways associated with Aβ production and allows for a deeper understanding of the complex pathogenesis of AD.

FUNDING

This work was supported by the National Health and Medical Research Council of Australia [grant number APP1082600]; and the Australian Research Council [grant number DP130103207].

Abbreviations

     
  • AD

    Alzheimer's disease

  •  
  • AP

    adaptor protein

  •  
  • APH-1

    anterior pharynx-defective-1

  •  
  • APLP

    amyloid precursor-like protein

  •  
  • Apo

    apolipoprotein

  •  
  • APP

    amyloid precursor protein

  •  
  • Arf6

    ADP-ribosylation factor 6

  •  
  • amyloid β-peptide

  •  
  • BACE1

    β-site APP-cleaving enzyme 1

  •  
  • CTF

    C-terminal fragment

  •  
  • ER

    endoplasmic reticulum

  •  
  • GGA

    Golgi-localized γ-ear-containing Arf-binding

  •  
  • GWAS

    genome-wide sequencing studies

  •  
  • KPI

    Kunitz protease inhibitor

  •  
  • PM

    plasma membrane

  •  
  • PS

    presenilin

  •  
  • PTB

    phospho-tyrosine binding

  •  
  • sAPP

    soluble APP

  •  
  • SNX

    sorting nexin

  •  
  • TGN

    trans-Golgi network

  •  
  • Vps

    vacuolar protein sorting

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