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Keywords:

  • Aβ;
  • Alzheimer disease;
  • function;
  • mechanisms;
  • sAPPs

Abstract

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

J. Neurochem. (2012) 120 (Suppl. 1), 99–108.

Abstract

Amyloid peptide (Aβ) is derived from the cleavage of amyloid precursor protein (APP), which also generates the soluble peptide APPβ (sAPPβ). An antagonist and major APP metabolic pathway involves cleavage by alpha secretase, which releases sAPPα. Although soluble Aβ oligomers are neurotoxic, Aβ monomers share similar properties with sAPPα. These include neurotrophic and neuroprotective effects, as well as stimulation of neural-progenitor proliferation. The properties of Aβ monomers and the neurotrophic capacity of sAPPβ to stimulate axonal outgrowth suggest that Aβ production is not deleterious per se. Consequently, therapeutic strategies for Alzheimer’s disease that are targeted at Aβ-cleaving enzymes should modulate rather than inhibit Aβ generation. These strategies should focus on the factors that induce the conversion of Aβ monomers into toxic soluble oligomers. Another interesting therapeutic approach is to focus on the mechanisms of the different properties of sAPPα. Indeed, increasing sAPPα levels could shift proliferating cells towards tumorigenesis. In contrast to its neuroprotective effects, sAPPα is also able to activate microglia, leading to neurotoxicity. Understanding the mechanisms that underlie the different properties of sAPPα could therefore lead to the development of therapeutic strategies against Alzheimer’s disease, which could be curative as well as preventive.

Abbreviations used

amyloid peptide

AD

Alzheimer’s disease

APLP

APP-like protein

APP

amyloid precursor protein

HBS

heparin-binding sites

HSPG

heparan sulfate proteoglycan

KPI

Kunitz protease inhibitor

LTP

long-term potentiation

sAPPβ

soluble APP beta protein

One of the pathological hallmarks of Alzheimer’s disease (AD) is the extracellular amyloid deposits present in the brains of affected patients. These deposits are mainly composed of amyloid peptide (Aβ) which is 40 to 42 amino-acids in length and is derived from amyloid precursor protein (APP). APP is a single transmembrane protein with a long N-terminal domain and a short cytoplasmic tail. The APP family also contains the APP-like proteins 1 and 2 (APLP1 and APLP2) which share a large sequence similarity with APP although they lack the Aβ domain (Sprecher et al. 1993; Wasco et al. 1993). APLP1 is only expressed in the brain whereas APLP2 and APP are ubiquitous. APP is encoded by one single gene of 19 exons; three major isoforms are generated from alternative splicing of exons 7 and 8, and are defined by the number of amino-acids they contain. Isoforms of 770 and 751 amino acids have a Kunitz protease inhibitor (KPI) sequence in their N-terminal domain whereas isoform 695 is devoid of this sequence. Isoform 770 also contains an OX2-related domain. The KPI isoforms are expressed in all cell types apart from neurons, where isoform 695 is exclusively expressed.

Like other proteins, APP has post-translational modifications in its ectodomain including N- and O-glycosylations, sulfations, and phosphorylations. APP is metabolized by two distinct antagonist pathways. The major pathway is driven by an alpha secretase cleavage, which releases the soluble N-terminal ectodomain (sAPPα). This occurs within the Aβ sequence, and thus avoiding Aβ generation (Fig. 1). sAPPα is already present early in brain development (Löffler and Huber 1992). APLP1 and APLP2 are also processed by alpha secretase. Alpha secretase cleavage is performed by two disintegrin metalloproteases (ADAM 10 and ADAM 17) (Vincent and Govitrapong 2011). In the alternative pathway, Aβ is generated from sequential cleavage of APP by beta secretase, then gamma secretase and presenilin is a component of the gamma secretase complex. Cleavage by β secretase generates the soluble APP beta protein (sAPPβ) which shares the same sequence as sAPPα apart from the last C-terminal amino-acids (Fig. 1). After cleavage of Aβ peptide, the APP intracellular domain detaches from the cell membrane and enters the nucleus to regulate gene expression (Fig. 1).

image

Figure 1.  APP metabolites. APP protein (695 amino acids) is processed via two alternative pathways, resulting in cleavage by α secretase to generate sAPPα or β secretase to generate sAPPβ. Following cleavage by β secretase, additional cleavage by γ secretase releases the Aβ peptide and the intracellular domain (AICD) detaches from the cytofacial leaflet.

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In AD pathology, the Aβ peptide induces the formation of soluble neurotoxic oligomers before triggering the formation of fibrils in amyloid deposits. In familial Alzheimer’s diseases (FAD), there is an increase of Aβ cleavage caused by an inherited mutation in APP or presenilin. In sporadic diseases, an increase of cleavage occurs in some patients who have high level of beta secretase caused by a deficiency of the miRNAs that control its expression (Hebert et al. 2008). An increase of Aβ peptide in sporadic diseases is also associated with a clearance of Aβ caused by a decrease of Aβ-degrading enzymes (Miners et al. 2008). Several species of Aβ peptides have been identified in the brain and many authors have reported the presence of N- and C-terminal truncated isoforms (Portelius et al. 2011). Of these, Aβ1–40 is the major isoform. However, less abundant species, Aβ1–42, and its N-terminally truncated isoforms are the more aggregant and neurotoxic (Portelius et al. 2011).

Aβ peptide

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

Properties of Aβ monomers

The Aβ peptide has been studied for some time to identify its toxic effects on neurons. Currently, the neurotoxicity of Aβ is thought to result from self association of Aβ1-42 monomers or its truncated isoforms into soluble oligomers. However, this cleavage in the Aβ peptide occurs during brain embryogenesis and seems to be required for normal brain development (Hartmann et al. 1999; Herms et al. 2004; Guenette et al. 2006). This suggests that the Aβ peptide is not always associated with neurotoxicity, particularly when at low concentrations which do not allow the formation of oligomers. The Aβ peptide may be neuroprotective; a peptide of the 28 first amino acids of Aβ enhances the survival of hippocampal neurons in vitro (Whitson et al. 1989). Furthermore, Aβ monomers induce the survival of developing neurons under trophic-factor deprivation and protect mature neurons against excitotoxic cell death (Giuffrida et al. 2009). The Aβ peptide has also been reported to be neurotrophic when added at low concentrations to undifferentiated hippocampal neurons (Yankner et al. 1990). In addition, the Aβ1–40 and Aβ1–42 isoforms stimulate proliferation of primary neural progenitor cells isolated from rat E18 cerebral cortices (Chen and Dong 2009). Furthermore, Aβ1–40 induces the differentiation of neural progenitor cells into neurons at the end of S-phase whereas Aβ1–42 drives the differentiation towards the astrocyte lineage (Chen and Dong 2009). At least, neuronal activity can generate the formation and the secretion of Aβ in hippocampal slices. Aβ depresses excitatory synaptic transmission onto neurons which in turn decreases the neural activity, in a negative feedback regulation (Kamenetz et al. 2003).

The properties of Aβ monomers including the neurotrophic and neuroprotective effects, the proliferation of the neural progenitor cells, as well as the involvement in synaptic function imply that cleavage of the Aβ peptide is of key physiological importance in the central nervous system.

Cell-surface receptors and Aβ peptide

The mechanism by which Aβ peptide targets a signal to neurons remains an open question. Extracellular Aβ uptake occurs through different pathways of entry through distinct cell-surface receptors, including NMDA receptor, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors, low-density lipoprotein receptor-related protein, alpha7 nicotinic acetylcholine receptor, and receptor for advanced glycation end products (Giri et al. 2000; Wang et al. 2000; Bi et al. 2002; Bu et al. 2006; Zhao et al. 2010). In vitro and in vivo mouse AD models show that the uptake of Aβ oligomers through these receptors is associated with increased neurotoxicity. However, the uptake of Aβ monomers has not been reported to occur through these receptors.

Aβ oligomers have also been described to interact with the cellular prion protein leading to a blockage of hippocampal long-term potentiation (LTP) and impairments in rodent spatial memory (Lauren et al. 2009). Recently, Aβ1-42 acting through the p75 neurotrophin receptor has been shown to stimulate neurogenesis in the sub-ventricular zone in adult mice (Sotthibundhu et al. 2009). It remains to be determined whether the p75 receptor is also involved in neurotrophic as well as neuroprotective effects.

sAPPα

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

sAPPα shares several domains with the N-terminal part of APP (Fig. 2). The 695 isoform contains 612 amino-acids with 12 cysteines. The crystal structure of residues 18–350 has three disulfide bonds which determine its secondary structure (Rossjohn et al. 1999). Mutation of one disulfide bridge alters the ectodomain structure and its APP function (Young-Pearse et al. 2007). The main domains of sAPPα could be related to four heparin-binding sites (HBS). One of these regions can bind to copper, another resembles the binding site of a growth factor while another domain can bind to zinc only (Fig. 2).

image

Figure 2.  Schematic representation of the main domains of sAPPs. The growth factor-like domain (GFLD) (28–123) also contains a heparin binding site (HBS) involved in neurite outgrowth (96–110). Another sequence (319–335) involved in neurite outgrowth is also a HBS (316–346). Two other HBS are present; one (131–166) shares the capacity to bind copper (135–155), and the other (382–447) is active in neuroprotection. The zinc-binding domain has no HBS. The C-terminal part of sAPPα (591–612) and the GFLD (28–123) contains two neuroprotective domains. The position of the KPI domain is indicated. Amino-acid numbering is for APP 695.

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sAPPα and animal models

Transgenic mice with neuronal over-expression of human APP mutated at the alpha secretase site show the following characteristics: increased aggressiveness, disturbed responses to kainic acid and NMDA, behavior deficits, and premature death (Moechars et al. 1996, 1998). In a more recent study, the abnormalities of APP-knock-out mice – such as reduced brain and body weight, reduced grip strength, impaired spatial memory and LTP – are lost in sAPPα knock-in mice (Ring et al. 2007). These models confirm that the beneficial effects of sAPPα are powerful (Table 1). The importance of sAPPαin vivo is also observed in Caenorhabditis elegans where expression of the ectodomain of the sAPPα ortholog, APL-1, reverses the larval lethality of nematodes carrying APL-1 mutations (Hornsten et al. 2007).

Table 1.   Animals models related to sAPPα and sAPPβ cited in the text
GenotypeLethalityPhenotypeReference
APP/RK Tg mice (mutated α-secretase site)Premature deathIncreased aggressiveness Decreased responses to NMDA Decreased locomotor activity Hypersensitivity to epileptic seizuresMoechars et al. (1996, 1998)
APP KO Tg mice Reduced body weight Reduced grip strength Reduced locomotor alterations Deficits in spatial learning and LTP deficit in aged mice Deficits in copper homeostasisMüller et al. (1994); Li et al. (1996); Heber et al. (2000)White et al. (1999)
sAPPα KI Tg mice (onto APP KO mice) Rescue of APP KO phenotypeRing et al. (2007)
APP/APLP2 KO Perinatally lethal von Koch et al. (1997)
Tg mice  Heber et al. (2000)
sAPPα DM Tg mice (sAPPα KI onto APLP2 KO mice)Rescue of the post-natal lethality of the majority of APP/APLP2 KO miceDeficits in spatial learning and LTP Deficits in post-natal synaptic maturation and maintenance Deficits in neuromuscular transmissionWeyer et al. (2011)
sAPPβ KI Tg mice (onto APLP2 KO mice)Perinatally lethal Li et al. (2010)
APL-1 KO Tg Caenorhabditis elegans (APP ortholog)Larval lethality Hornsten et al. (2007)
APL-1 KO Tg  Caenorhabditis elegans with neuronal expression of soluble APL-1 extracellular domainRescue of the larval lethality Hornsten et al. (2007)

sAPPα and neuritogenesis

Previous studies have suggested that components of the extracellular matrix, including the heparan sulfate proteoglycans (HSPGs), bind to sAPPα (Schubert et al. 1989; Klier et al. 1990; Narindrasorasak et al. 1991; Small et al. 1992). The use of HSPGs as a substrate, together with APP, stimulates neurite outgrowth from chick sympathetic neurons and mouse hippocampal neurons (Small et al. 1994; Clarris et al. 1997). Among the four HBS of sAPPα (96–110; 131–166; 316–346; 382–447), the region 96–110 is involved in the regulation of neurite outgrowth (Clarris et al. 1994; Small et al. 1994). This domain is active after cyclization of cysteines 97 and 105 and strongly binds to HSPGs (Small et al. 1994; Kaden et al. 2008). The physiological response following the interaction of APP with HSPGs varies according to HSPG type (Small et al. 1992; Williamson et al. 1995, 1996). The sAPPα region 319–335, which contains the RERMS sequence, is also involved in neurite outgrowth (Jin et al. 1994; Ninomiya et al. 1994). In a recent study, we added sAPPα to embryonic cortical neurons at one day in vitro and observed a decrease of cell adhesion after 24 h (Chasseigneaux et al. 2011). This was followed 48 h later by a decrease of dendrites and an increase of axon outgrowth, similar to that observed with the addition of heparan sulfate (Lafont et al. 1992, 1993). We demonstrated that this effect is independent from the post-translational modifications present on sAPPα. It remains to be determined whether this physiological response depends upon secreted HSPGs in the conditioned medium. Interestingly, the same effect was also observed with sAPLP2 but not with sAPLP1 in neural stem cell-derived neurons (Gakhar-Koppole et al. 2008).

sAPPα and proliferation

Crystallization studies of the sAPPα residues 18–350 have identified structural similarities with cysteine-rich growth factors (Rossjohn et al. 1999). This suggests that sAPPα functions as a growth factor in vivo. Indeed, sAPPα is involved in the proliferation of non-neuronal cells as it restores the cell growth of fibroblasts in which expression of APP has been down-regulated, and also stimulates the growth of thyroid epithelial cells (Saitoh et al. 1989; Pietrzik et al. 1998). Concerning neuronal cells, sAPPα has been shown to stimulate the proliferation of neural stem cells from embryonic brains (Hayashi et al. 1994; Ohsawa et al. 1999). More recently, we have shown that sAPPα potentiates the effect of epidermal growth factor on the proliferation of adult neuroblasts from the sub-ventricular zone both in vitro and in vivo (Cailléet al. 2004). We observed a similar effect with the ectodomain of APLP2, but not with APLP1 (Cailléet al. 2004). This suggests that there is a redundancy between secreted sAPPα and sAPLP2. In rodents, neuroblasts from the sub-ventricular zone represent a source of newly formed neurons that are destined to form the olfactory bulb; in primates these cells give rise to neurons that are destined to form the amygdala and the pyriform cortex (Bernier et al. 2002). The sAPPα domain that is responsible for neuroblast proliferation is yet to be identified.

Cellular proliferation induced by sAPPα has also been observed in colonic carcinoma, as well as in pancreatic- and prostate-tumor cells (Meng et al. 2001; Hansel et al. 2003; Takayama et al. 2009). An increase of APP expression has been observed in malignant brain tumors such as glioblastoma multiforme. However, it has yet to be determined whether sAPPα is also involved in glioblastoma cell proliferation (Culicchia et al. 2008). The action of sAPPα on cell division raises the question of whether tumor proliferation could occur if expression of alpha secretase is strongly increased.

sAPPα and LTP

Previous reports have shown that a 17 mer peptide (residues 319–335) of sAPPα– which has characterized neurotrophic properties – increases both synaptic density and memory retention (Roch et al. 1994). In addition, behavior studies have shown that sAPPα has potent memory-enhancing effects (Meziane et al. 1998). As expected from the memory-test results, sAPPα increases LTP and facilitates in vitro tetanically evoked NMDA receptor-mediated currents (Ishida et al. 1997; Taylor et al. 2008). sAPPα appears to promote memory consolidation more than acquisition. As observed for sAPPα-induced neurite outgrowth, the KPI sequence of sAPPα does not appear to play a role in memory potentiation (Meziane et al. 1998). sAPPα alone is sufficient to correct the impairments in spatial learning and LTP that are present in APP knock-out mice – as observed in sAPPα knock-in mice (Ring et al. 2007). These reports suggest that sAPPα is strongly involved in cognitive performance.

sAPPα and metal homeostasis

The APP ectodomain – which is downstream to the HBS residues 96–110 involved in neurite outgrowth – can bind copper between residues 135 and 155 and zinc between residues 181 and 200 (Bush et al. 1993; Hesse et al. 1994). Binding of copper in the ectodomain of APP and APLP2 reduces bound copper II to copper I, which in turn regulates degradation of the glypican-1 heparan sulfate in vivo (Multhaup et al. 1996). This suggests a close spatial conformation between the copper-binding site – where the free radicals are generated – and the HBS interacting with the heparan sulfate – where the free radicals allow degradation of the glycan chains (Cappai et al. 2005). Binding to zinc II increases the affinity for heparin by two to four fold in vitro (Multhaup et al. 1994). Together with heparan sulfate, zinc increases the inhibition of coagulation factor XIa through sAPPα isoforms containing the KPI domain which is analogous to the protease inhibitor nexin-2 (Van Nostrand 1995). The high affinity of the copper- and zinc-binding domains for their respective metals suggests that APP/APLP2 and sAPPα/sAPLP2 may function as neuronal metallotransporters and metallochaperones which regulate metal homeostasis. Indeed, the binding of copper to the ectodomain of APP and APLP2 but not of APLP1 results in an efflux of copper when sAPPα and sAPLP2 are secreted (Treiber et al. 2004). Metal homeostasis is also important for the cleavage of Aβ peptides because an increase of copper in the brain leads to a decrease of Aβ cleavage. Furthermore, AD APP23 mice receiving drinking water supplemented with copper for 3 months show a decrease of Aβ production (Bayer et al. 2003).

sAPPα, homo and heterodimerization

Homodimerization of APP and heterodimerization with its APLP homologs promote intercellular adhesion (Soba et al. 2005). The formation of APP dimers depends upon a GxxxG motif within the APP transmembrane domain and influences the cleavage of the Aβ peptide (Munter et al. 2007; Kienlen-Campard et al. 2008). However, a domain close to the N-terminal domain of APP has also been reported to be involved in APP dimerization (Soba et al. 2005). Homophilic interactions of the APP ectodomain through hydrophobic residues have been reported and are dependent on the disulfide bonded loop between residues Cys98 and Cys105 (Kaden et al. 2008). Although this has been demonstrated for the domain extending from residues 18 to 350 of the APP protein, one can assume that dimerization of sAPPα occurs through the same interactions. The central region of the APP and APLP1 ectodomains has also been proposed to contribute to dimerization (Lee et al. 2011). Other studies derived from modeling of the small-angle X-ray scattering have proposed that dimerization of sAPPα occurs through an interaction with heparin with a sAPPα : heparin ratio of 2 : 1 (Gralle et al. 2006). It is possible that the binding of HSPGs to sAPPα, which is responsible for the increase of neurite outgrowth, occurs through dimerization of sAPPα.

sAPPα and neuroprotection

An important property of sAPPα is its neuroprotective effects; it has potent neuroprotective actions against glutamate neurotoxicity, Aβ peptide-induced oxidative injury, and glucose deprivation (Mattson et al. 1993; Goodman and Mattson 1994; Barger and Harmon 1997). sAPPα can also protect PC12 cells from other deleterious insults such as epoxomicin or UV irradiation (Copanaki et al. 2010). When infused 10 min after a period of ischemia in vivo, sAPPα protects hippocampal neurons against ischemic injury (Smith-Swintosky et al. 1994). The in vitro neuroprotective effects against glutamate and Aβ toxicity are attributable to the C-terminal part of sAPPα (residues 591–612), and heparinases greatly reduce this action (Furukawa et al. 1996a). More recently, two domains able to bind HSPGs (residues 28–123 and 316–498) were found to be involved in neuroprotection against traumatic brain injury in rats, suggesting that HSPGs could mediate this response (Corrigan et al. 2011). The neuroprotective action of sAPPα is always observed in vitro in the absence of microglial cells or in vivo when inflammation has not yet developed.

sAPPα, peripheral cells, inflammation, and immunity

APP is expressed in all cell types, including peripheral blood cells. Human platelets stimulated by thrombin or ionomycin secrete sAPPα derived from APP 751/770. These sAPPα isoforms inhibit coagulation factor XIa, which implies that they have an important role in blood coagulation (Cole et al. 1990; Van Nostrand et al. 1991). sAPPα is also secreted by CD4 and CD8 human T lymphocytes following their stimulation (Monning et al. 1990, 1992). The stimulation of these lymphocytes induces APP transcription and secretion over a time frame that is similar that for interleukin 2. The main sAPPα isoform released from the stimulated lymphocytes contains a splice of exon 15 – which is a leukocyte-specific isoform (L-APP) – and the KPI domain (Monning et al. 1992). Examples of activated T lymphocytes in vivo have been reported in polymyositis, which is an inflammatory myopathy disease (Monning et al. 1990). As with lymphocytes, stimulation of microglial cells and astrocytes – which mediate immune reactions in the brain – leads to the expression of APP and the secretion of sAPPα, including an L-APP isoform (Monning et al. 1992). The release of sAPPα from activated lymphocytes, microglia, and astrocytes suggests that this protein is associated with immune defense mechanisms in the PNS and CNS.

Conversely, sAPPα is also able to stimulate microglia leading to the release of neurotoxic cytokines. This action is blocked by the prior incubation of sAPPα with apolipoprotein E3 but not apolipoprotein E4, which is a risk factor for sporadic AD (Barger and Harmon 1997). These observations imply that therapeutic strategies to stimulate the formation of sAPPα should take place very early in the AD process, before the development of inflammation, especially for patients with the ApoE4 allele.

Mechanisms of sAPPα properties

Although the effects of sAPPα are well known, the mechanisms that underlie these properties are yet to be elucidated. The importance of post-translational modifications in the properties of sAPPα have been poorly investigated, though we have shown that they are not involved in its neurotrophic action (Chasseigneaux et al. 2011). sAPLP2 has a strong sequence homology with sAPPα and shares similar properties, such as the increase of the neurite outgrowth, the proliferation of adult neuroblasts and the involvement in copper homeostasis.

We and others have shown that mitogen-activated protein kinase/extracellular signal-regulated kinase is activated in response to sAPPα (Greenberg and Kosik 1995; Gakhar-Koppole et al. 2008; Rohe et al. 2008). Other studies have reported that phosphatidylinositol-3 kinase, Akt kinase, and p42/p44 mitogen-activated kinases mediate both the neurotrophic and excitoprotective actions of sAPPα (Cheng et al. 2002). We have recently reported that sAPPα-induced axon elongation does not occur in primary neurons from mice homozygous invalidated for Egr1, suggesting that this effect specifically requires Egr1 signaling (Chasseigneaux et al. 2011). The same transgenic mice showed a deficit in late and long-term memory (Jones et al. 2001). Because of the positive effects of sAPPα on LTP and spatial memory, the expression of Egr1 necessary for LTP may also depend upon sAPPα.

Previous studies have shown that sAPPα stimulates membrane-bound guanylate cyclase, regulates the calcium homeostasis, decreases the NMDA receptor currents, and increases potassium-channel conductance (Barger and Mattson 1995; Barger et al. 1995; Furukawa et al. 1996b). How these effects are mediated by the different properties of sAPPα has not yet been defined.

sAPPα could compete with cell-surface APP for interaction with integrin β1, leading to an increase in neurite outgrowth via integrin signaling (Young-Pearse et al. 2008). However, other studies have shown that sAPPα binds to the cell surface of three different cell lines (Hoffmann et al. 1999), and we observed that sAPPα binds to primary neurons (Fig. 3). The membrane partners involved in this interaction and their requirement for sAPPα functions still need to be determined.

image

Figure 3.  sAPPα binding sites are present on neuronal membranes. Confocal section of mouse cortical neurons at 5 days in vitro fixed and incubated with sAPPα fused to a Fc tag. After washing, neurons were incubated with an anti-Fc tag antibody coupled to Cy3. Arrows show details of the membrane where sAPPα binds. Scale bar: 10 μm.

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sAPPβ

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

Only a few studies have investigated the properties of sAPPβ. This protein is released after cleavage by beta secretase and shares the same sequence as sAPPα apart from the last 16 C-terminal amino-acids. The neuropotective effects of sAPPβ against glucose deprivation, excitotoxicity, and β amyloid peptide are 50- to 100-fold less potent (Furukawa et al. 1996a; Barger and Harmon 1997). Furthermore, sAPPβ does not appear to reduce cell death induced by the proteasome inhibitor, epoxomicin (Copanaki et al. 2010). In contrast with sAPPα, sAPPβ is not involved in LTP. This suggests that the last 16 C-terminal amino-acids of the sAPPα protein are involved in both neuroprotection and LTP (Taylor et al. 2008). In a recent study, sAPPβ knock-in mice were unable to rescue the perinatal lethality of double APP and APLP2 knock-out mice – in contrast with sAPPα knock-in mice – which further suggests functional differences between these two sAPPs (Li et al. 2010; Weyer et al. 2011). In contrast with APP and APLP2 knock-out mice, the expression of transthyretin and Klotho in sAPPβ knock-in mice was not decreased at birth especially in the liver which was devoid of any APLP1 (Li et al. 2010). Transthyretin protects APP23 transgenic mice from the behavioral changes caused by Aβ toxicity. Transthyretin release by sAPPβ may therefore protect against Aβ neurotoxicity (Buxbaum et al. 2008). To better understand the actions of sAPPβ, its cell-surface receptor and the intracellular pathways driving the expression of transthyretin and Klotho require further investigations.

sAPPβ contains the domains required to promote neurite outgrowth, and like sAPPα, we observed that sAPPβ decreases cell adhesion and increases axonal outgrowth (Chasseigneaux et al. 2011). In a recent report, sAPPβ induced a rapid neural differentiation of human embryonic stem cells more efficiently than sAPPα (Freude et al. 2011). These effects of sAPPβ on axon elongation and neural differentiation suggest that this protein cannot be deleterious per se. Like sAPPα, sAPPβ stimulates microglia with the same efficiency, and this effect is related to the N-terminal domain upstream to residue 444, which is common to both sAPPs (Barger and Harmon 1997). Therefore, in the presence of microglia, sAPPβ may have similar neurotoxic effects to sAPPα. Indeed, in the apoptosis of peripheral neurons induced by deprivation of growth factors, sAPPβ binds to the DR6 receptor triggering cell death (Nikolaev et al. 2009). Overall, the functions that are related to the common domains of sAPPα and sAPPβ are identical, and are not affected by differences in the 16 C-terminal amino-acids of these two APPs. However, functions such as neuroprotection and LTP are affected by these differences.

Conclusions

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

Both Aβ monomers and sAPPα have similar properties; they increase neurite outgrowth in vitro, they are neuroprotective, and they stimulate proliferation of adult neural progenitors. In addition, the main metabolite released following beta secretase cleavage, sAPPβ, has similar neurotrophic properties to sAPPα, and thus is not deleterious per se. This suggests that therapeutic strategies for AD that are targeted at Aβ cleavage enzymes should aim to modulate rather than inhibit the generation of Aβ. Potential therapies should also focus on the factors that induce the conversion of Aβ monomers into toxic soluble oligomers.

Increasing the generation of sAPPα is an interesting alternative approach. However, the two alpha secretase enzymes (ADAM 10 and ADAM 17) are not specific to APP and the physiological consequences of the release of other transmembrane I receptor ectodomains have not yet been investigated (Mills and Reiner 1999). Although the capacity of sAPPα to stimulate the division of adult neural precursors from the sub-ventricular zone is of interest to treat neurodegenerative processes, it cannot be excluded that a high increase of sAPPα could favor the shift of some dividing cells towards tumorigenesis (Meng et al. 2001; Hansel et al. 2003; Takayama et al. 2009). In addition, the stimulation of microglia by both sAPPα and sAPPβ suggests that a strategy promoting the formation of sAPPα should be either preventive or occur at the early stages of AD, before the development of inflammation. Understanding the mechanisms of action of sAPPα– including cell-surface receptors and the signaling pathways associated with each function of sAPPα– is therefore of interest to develop new therapeutic approaches, which could be curative as well as preventive.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References

The authors declare no conflict of interests.

References

  1. Top of page
  2. Abstract
  3. Aβ peptide
  4. sAPPα
  5. sAPPβ
  6. Conclusions
  7. Conflict of interest
  8. References
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