Review
Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease Liang Hong1, Han-Chang Huang1,2, Zhao-Feng Jiang1,2 1
Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, China, College of Arts and Science, Beijing Union University, China
2
Amyloid-beta (Abeta) peptide is the original causative factor of Alzheimer’s disease (AD) according to the amyloid cascade hypothesis. The ubiquitin–proteasome system (UPS), the major intracellular protein quality control system in eukaryotic cells, is related to AD pathogenesis. There is growing evidence showing that there is a tight relationship between Abeta and UPS and this relationship plays an important role in AD pathogenesis. This article reviews the relationship between Abeta and the UPS in terms of the following three aspects: the interaction of the two factors, the ubiquitinating process of Abeta, and impact of dysfunctional UPS on Abeta production. The impairment in the UPS in AD could affect the degradation of Abeta and lead to an abnormal accumulation of Abeta. At the same time, Abeta inhibits the proteasomal activity and subsequently leads to impairment of multivesicular bodies (MVB) sorting pathway, forming an interacting relationship between Abeta and UPS. Mutant ubiquitin (Ub) and ubiquitin-like (UBL) ubiquilin-1 are related to Abeta accumulation. Meanwhile E2 conjugating enzymes, E3 ligases, and de-ubiquitinating enzymes, all of which function in the ubiquitination process, play a pivotal role in the proteasomal degradation of Abeta. Ubiquitin–proteasome system has an immense impact on the amyloidogenic pathway of amyloid precursor protein (APP) processing that generates Abeta. Upregulation in proteasomal degradation of BACE1 and components of gamma-secretase leads to decreased Abeta accumulation. A deep look into the mechanism underlying the interplay between Abeta and UPS may provide alternative therapeutic targets and lead to new drugs and therapies. Keywords: Alzheimer’s disease, Amyloid-beta, Degradation, Proteasome, Ubiquitin
Introduction Amyloid-beta (Abeta) and Alzheimer’s disease (AD) A quarter of a century of research on Abeta has produced a wealth of evidence that its accumulation in brain regions serving memory and cognition contributes strongly to the development of AD.1 The amyloid cascade hypothesis, a well known hypothesis describing the pathogenesis of AD, suggests that Abeta accumulation is the earliest pathological change in AD. Amyloid-beta is the central molecule in the pathogenesis of this disease. Recent studies further suggest that intracellular Abeta accumulation plays an important role in AD. Intracellular Abeta42 accumulation occurs in the pyramidal neurons of the hippocampus and entorhinal cortex long before the emergence of Abeta plaques and paired helical filaments in the brains of AD patients.2 So, intracellular Abeta may be even Correspondence to: Zhao-Feng Jiang, Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, 197# Beitucheng West Road, Haidian District, Beijing 100191, China. Email: [email protected]
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more important than extracellular Abeta, and intraneuronal Abeta represents an alternative therapeutic target. Growing evidence shows that deficiency of the Abeta clearance may be the predominant cause of late-onset AD, which accounts for the largest percentage of AD cases. Now that intracellular Abeta is the most important form of Abeta, degradation of Abeta by intracellular pathway shall be of special importance to the pathogenesis of AD. Thus, the ubiquitin– proteasome system (UPS), as the main intracellular proteolytic pathway in eukaryotic cells, has been paid extensive attention.
Ubiquitin–proteasome system and AD Ubiquitin–proteasome system, the major protein quality control system in eukaryotic cells, degrades misfolded or other abnormally modified proteins. Most proteins designated for destruction by UPS are first tagged by a polyubiquitin chain. This ubiquitination process is ATP-dependent and occurs in a process containing three steps. First, ubiquitin (Ub) is
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activated by an E1 ubiquitin-activating enzyme; second, activated Ub binds to an E2 conjugating enzyme; and finally the Ub moiety binds to a lysine residue within the targeted protein via an E3 ligase. The polyubiquitinated substrates are then recognized, unfolded, and degraded at the 26S proteasome.3 The 26S proteasome is a multi-subunit complex composed of a central 20S catalytic core particle (20S proteasome) and one or two 19S regulatory particles. The 20S proteasome has a cylindrical structure composed of two outer alpha-rings and two inner beta-rings. Each alpha-ring is composed of seven alpha-subunits and each beta-ring is composed of seven betasubunits.4 The two outer rings close the interior of the barrel shaped complex, whereas the inner two rings consist beta-subunits including three subunits with catalytic activity. These three active subunits, which are referred to as beta1, beta2, and beta5, have caspase-like activity that cleaves substrates behind acidic residues, trypsin-like activity that cleaves substrates after basic residues, and chymotrypsin-like activity that cleaves substrates behind hydrophobic residues, respectively.5 A wealth of evidence shows that perturbation in the UPS plays a causative role in AD. The activity of proteasome is significantly decreased in the hippocampus, parahippocampal, and middle temporal gyri, and the inferior parietal lobule of Alzheimer’s patients.6 What is more, defective proteolysis may cause the synaptic dysfunction observed early in AD since protein degradation regulated via the ubiquitin proteasome system plays a critical role in synaptic plasticity.7 Besides Abeta accumulation, the perturbation of UPS correlates with other AD characteristics such as tau hyper phosphorylation and autophagy, making its role in the pathogenesis of AD very important. The biochemical and morphologic research done by Tai et al. on the location of tau in control and AD cortices demonstrates that in AD tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals and that the accumulation of these hyperphosphorylated tau oligomers is associated with the increase of ubiquitinated substrates and proteasome components. These results suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that damages synapses in AD.8 According to the study by Cecarini et al., the over-expression of the amyloid precursor protein (APP) AD-linked mutant isoform in human SH-SY5Y neuroblastoma cells correlates with a remodeled pattern of protein degradation with marked inhibition of proteasome activities and impairment in the autophagic flux.9 Although some proteins can be degraded by 20S proteasome in a way independent of ATP and ubiquitin,10 the degradation of Abeta requires ATP
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and the ubiquitination process. So, elucidating the relationship between Abeta and UPS, two most crucial factors in AD, is of great importance to the understanding of the pathogenesis of this common and severe neurodegenerative disorder and to the searching of novel pharmacological targets for AD treatment. Here we review the current knowledge of the relationship between Abeta and UPS in terms of three aspects: (1) the interplay between Abeta and UPS; (2) the impact the proteins involved in the process of ubiquitination, including ubiquitin-like (UBL) proteins and ubiquitinating enzymes, have on Abeta accumulation and the reverse effect Abeta could have on them; and (3) the relationship between UPS and Abeta production.
Interplay between Abeta and UPS The relationship between Abeta and proteasome has been paid great attention since the detection of Ub in senile plaques by Perry et al. in 1987.11 It was once assumed that proteasome might play no physiologic role in Abeta degradation since the proteasome is localized to the cytosol and Abeta is produced in lumenal compartments. However, some later reported experimental evidence suggests that Abeta42 can diffuse passively from the lumen of the endoplasmic reticulum (ER) into the cytosol, where it is degraded by the proteasome and insulin degrading enzyme (IDE).12 It turns out that UPS degrades Abeta and is at the same time effected by Abeta. There is a doubleway relationship between Abeta and UPS as described below.
Impact of UPS on Abeta Ubiquitin–proteasome system degrades Abeta and has immense effect on Abeta toxicity. In a research using primary cultures of cortical neurons and astrocytes, when the proteolytic activity of the 26S proteasome was inhibited with lactacystin, there was a marked decrease in Abeta42 degradation. This suggests that Abeta, in both astrocytes and neurons, could be a possible substrate of this enzymatic complex.13 Alterations in the Ub-proteasome pathway could affect the degradation of Abeta, leading to an abnormal Abeta accumulation.13 Thus, the formation of amyloid plaques in AD patients could be the product of ubiquitin-mediated protein degradation defects.
Impact of Abeta on UPS Amyloid-beta inhibits the proteolytic activities of the 26S proteasome.14 It is found that Abeta25–35 and Abeta42 produce a significant increase in Ub-protein conjugates and in the expression of the Ub-activating enzyme E1 in neurons.13 Intraneuronal accumulation of Ub-protein conjugates is a pathological feature of AD. It is proposed that the accumulation of ubiquitinated species in AD is a result of the inhibition of
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proteasome activity induced by Abeta peptides.15 Once, it was proposed that Abeta40 peptides localize inside the 20S subunit along the active proteolytic site and inhibit the beta5 chymotrypsin-like activity of the proteasome.16 However, a recent research shows that aggregated forms of Abeta42 are competitive substrates for the chymotrypsin-like activity of the human 20S proteasome. Hence the impairment of proteasomal function induced by Abeta may arise from the competition of natural proteasomal substrates with increasing concentrations of toxic oligomeric Abeta peptides within the cells of patients with AD.15 Inhibition of UPS by intraneuronal Abeta42 causes such consequences as the impairment of multivesicular bodies (MVB) sorting pathway.14 Since MVBs are described as important vesicles in retrograde transport, appearing to carry substance from neuronal terminals to the cell body for signaling and/or degradation in lysosomes, their impairment might provide insight into Abeta toxicity on neuronal system function.
Amyloid-beta and Ubiquitination Mutant Ub and ubiquilin A frameshift mutant of the Ub protein, UBB(z1), which accumulates in an age-dependent manner as a result of molecular misreading, contributes to neuropathology in AD. The UBB(z1) protein has been found in the brains of AD patients.17 Proteomic profile analysis shows that in UBB(z1) transgenic mice, protein changes in the brain are remarkably similar to that in the human AD brain.18 UBB(z1) ’caps’ unanchored (that is, not linked to any substrates) polyubiquitin chains, which then act as dominant inhibitors of the 26S proteasome.19 It is reasonable to presume that this inhibition of 26S proteasome would affect degradation of Abeta, leading to abnormal Abeta accumulation. Surprisingly, in the research of van Tijn et al.20, however, a significant decrease in Abeta deposition and soluble Abeta42 was observed in APPPS1/UBB(z1) transgenic mice compared with in APPPS1 mice at 6 months of age. In other words, UBB(z1) decreases Abeta plaque formation in this transgenic mouse model of AD. The molecular mechanism underlying this decrease in Abeta deposition in APPPS1/UBB(z1) mice remains to be studied. In addition, the interaction between E2-25K/Hip-2 and UBB(z1) may be critical for the synthesis and accumulation of UBB(z1)-anchored polyubiquitin, which results in proteasomal inhibition and death of the neurons.21 Single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD. Its protein product, ubiquilin-1, functions as a molecular chaperone for APP and leads to Abeta accumulation. Ubiquilin proteins are UBL proteins. They belong to
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the family of UBL–ubiquitin-associated (UBL–UBA) proteins which are implicated in the regulation of the ubiquitin-dependent proteasomal degradation of cellular proteins.22 Protein levels of ubiquilin-1 are decreased in the brains of AD patients.23,24 It was found recently that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by mediating non-degradative ubiquitination on a single lysine residue in the cytosolic domain of APP.25
Ubiquitination enzymes The critical factors modulating both Abeta neurotoxicity and UPS in AD include several ubiquitination enzymes, such as E2-25K, HRD1, Parkin and UCHL1. A lot of findings about these critical molecules have been reported recently. (i) E2-25K. An unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2 is reported as a mediator of Abeta toxicity and is upregulated in AD.6 E2– 25K is an unusual member of the E2 conjugating enzyme family in that it is competent to catalyze Ub chain extension independent of E3 ligases.21 It functions upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta42 toxicity.6 It contains a UBA domain that is unique to human E2 conjugating enzymes. Ubiquitin-associated domains appear to be generally involved in interactions with ubiquitin. Although evidence suggests that the E2–25K UBA domain is important for polyubiquitylation activity, its precise function is currently unclear. A chimeric protein in which the UBA domain of E2–25K was fused to the E2 domain of yeast UBC4 showed no polyubiquitin synthetic activity, suggesting that polyubiquitylation by E2–25K is dependent on the relative conformations of the E2 and UBA domains and their specific interactions with each other.21 Interestingly, it was reported that an active site mutation, C92S or S86Y, or deletion of the UBA domain of E2– 25K eliminated Abeta neurotoxicity.26 It was also proposed that UBB(z1) interacts with the UBA E2–25K domain and participates in the polyubiquitylation process, producing the UBB(z1)-anchored polyUb chains. However, the details of the mechanism are not yet known.21 (ii) E3 ligases. The E3 Ub protein ligases play a pivotal role in the ubiquitination reaction because they mainly determine substrate specificity of the Ub conjugation reaction and are tethers that connect ubiquitin, substrate proteins, and the 26S proteasome. The relationship between E3 ligases and Abeta has been extensively studied recently. E3 ligases include parkin, HRD1, UCHL-1, etc. UCHL-1 also functions as a de-ubiquitinating enzyme. Parkin solubility is decreased in AD cortex. Parkin co-localization with intraneuronal Abeta42 is also detected in the hippocampus and cortex of AD patients.27 Incubation of Abeta42 cell lysates with ubiquitin, in the presence of parkin, results in the
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generation of Abeta–Ub complexes.28 In a research using SH-SY5Y and primary neuronal cells, wildtype parkin reverses intracellular Abeta accumulation and its negative effects on proteasome function.29 Accordingly, in a triple transgenic AD mouse model,30 it was found that injected lentiviral parkin ubiquitinates intracellular Abeta in vivo and that parkin expression decreases intracellular Abeta levels and extracellular plaque deposition. Taken together, parkin can ubiquitinate and clear Abeta and may be an alternative therapeutic target to reduce Abeta levels and to enhance clearance of Abeta-induced defects in AD. However, adverse results were also reported. Parkin null cortical neuronal/glial cultures are more resistant to Abeta42 toxicity than wild type,31 suggesting that parkin suppression may not be a risk factor for dementia of AD type. HRD1 is another E3 ligase. The levels of HRD1 are significantly decreased in the cerebral cortex of AD patients32 and are negatively correlated with Abeta production levels. A recent study investigated the protein levels of HRD1 and SEL1L in the NP-40 detergent-insoluble fraction of the controls and AD brains as well as correlation between HRD1 and Abeta. The results suggest that the decrease in HRD1 levels in AD is a result of its insolubilization, which may be involved in Abeta generation.33 Insolubilization of HRD1 protein causes dysfunction of HRD1, and this dysfunction results in increased Abeta levels. It is also reported that HRD1 promotes APP ubiquitination and degradation, resulting in decreased generation of Abeta.32 Unlike other E3 ligases, synoviolin upregulates Abeta production. The reason may be that it regulates the assembly of the gamma-secretase complex via the degradation of Rer1.34 The expression levels of F-box and leucine rich repeat protein2 (FBL2), a component of the SCF (Skp1–Cullin1–F-box protein) E3 Ub ligase complex, are decreased in the brains of AD patients.35,36 Both in vitro and in vivo experiments indicate that enhancement of FBL2 function, which could facilitate reduction of intraneuronal Abeta, is expected to be a novel therapeutic strategy for AD.2 The mechanism underlying the therapeutic effect of FBL2 may be that FBL2 regulates APP metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis.2 (iii) UCHL-1. Ubiquitin C-terminal hydrolase-1 (UCHL-1), an E3 ligase that is expressed mainly in neurons, also functions as a de-ubiquitinating enzyme. It stabilizes mono-ubiquitinated proteins in the meantime. UCHL-1 is downregulated in AD.37 In addition, down-regulation of both UCHL-1 mRNA and UCHL-1 protein is detected in the cerebral cortex in common forms of dementia with Lewy bodies (DLB) with accompanying AD changes.38 It is observed that the low
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protein levels of UCHL-1 are associated with high protein levels of BACE1 in sporadic AD brains. Concordant with this fact, a research using different cellular models such as neuroblastoma SH-SY5Y and NT(2) neuronal cells shows that Abeta42 treatment downregulates UCHL-1 and this down-regulation is dependent on NF-kappaB activation and on impaired BACE1 lysosomal degradation.39 Ubiquitin C-terminal hydrolase-1 accelerates BACE1 degradation and affects APP processing and Abeta production.40 In conclusion, potentiation of UCHL-1 might be able to reduce the levels of BACE1 and Abeta in brain, and UCHL-1 may be a novel target for AD drug development.
It is commonly proposed that among all the ubiquitination enzymes, E3s may be the favorite potential therapeutic targets because they mainly determine substrate specificity. However, technically, the high specificity of the Ub conjugation to a certain substrate is achieved through a combinatorial coding by E1s, E2s, and E3s.41 It would be better if drugs and therapies could target the combinatorial coding for Abeta ubiquitination. UCHL-1 is an attractive drug target for AD, because besides reducing Abeta production, UCHL-1 also plays an essential role in synaptic plasticity.42 It is showed that treatment with exogenous UCHL-1 can reverse the synaptic dysfunction in hippocampal slices from APP/PSEN1 mice or synaptic plasticity impairment in hippocampal slices from normal mice caused by treatment with oligomeric Abeta.43
Ubiquitin–Proteasome System and Abeta Production Abeta is derived by sequential proteolytic processing from a large trans-membrane protein, APP. Betaand gamma-secretase liberate by sequential cleavage the neurotoxic Abeta-peptide, whereas alpha-secretase prevents its generation by cleaving within the middle of the amyloid domain.44 Here we focus on the two secretases in the amyloidogenic processing pathway to elucidate the relationship between UPS and Abeta production.
Ubiquitin–proteasome system and betasecretase Lys203 and Lys382 are essential for the proteasomal degradation of beta-secretase (BACE1).45 This degradation of BACE1 is accelerated by UCHL-1.40 Furthermore, Fbx2 is a neuron-specific F-box protein that binds the Skp1 domain of the SCF (Skp1–Cullin1–Fbox protein) to E3 Ub ligase, forming SCFFbx2–E3 ligase complex. SCFFbx2–E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and enzymatic activity,
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coincidentally reducing Abeta levels and rescuing synaptic deficits.46
Ubiquitin–proteasome system and gammasecretase The critical components of the gamma-secretase complex include nicastrin (NCT), presenilin (PS), presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1). All of these components are degraded by the UPS.47,48 Presenilin is one of the key players in AD pathogenesis. Two homologous proteins, presenilins 1 and 2 (PS1 and PS2) are encoded by chromosomes 14 and 1, respectively. Presenilin proteins are endoproteolytically cleaved into two main fragments: the NTF (PS N-terminal fragment) and the CTF (PS Cterminal fragment). The two fragments are believed to constitute the core catalytic enzyme activity of gamma-secretase. Originally identified as a PS-interacting protein, ubiquilin is an important factor in regulating PS biogenesis and metabolism. High levels of ubiquilin might reduce gamma-secretase activity by decreasing the formation of PS fragments. It is showed that specific transcript variants of ubiquilin-1, which are genetically and functionally associated to AD, regulate proteasomal and aggresomal targeting of PS1.49 The UBL and UBA domains of ubiquilin-1 are involved in the degradation of PS.50 Ubiquilin-1 is also known to co-localize and interact with PS2 at least partially via its UBA domain.48 In addition, proteasome might function as the presenilinase that is responsible for PS endoproteolysis.51 High levels of ubiquilin decrease PEN-2 and NCT levels. What is more, inhibition of proteasomal APH1 degradation facilitated gamma-secretase cleavage of APP to generate Abeta.52 Apart from BACE1 and various components of gamma-secretase, a lot of other proteins involved in the APP metabolism, including full-length and Cterminal fragments of APP generated by beta-secretase (CTFbeta), are ubiquitinated and degraded in a proteasome-dependent manner. Many components of UPS regulate APP metabolism, showing a tight relationship between UPS and Abeta production.
Clinical Data, Drug Application, and Therapies on the Connection between Abeta and UPS The connection of Abeta and proteasome has been paid attention since the detection of Ub in senile plaques by Perry et al. in 1987.11 The disease-related proteins that form aggregates in other human neurodegenerative disorders are also found conjugated with ubiquitin, suggesting a common link between pathological protein-aggregation events in the nervous system and dysfunction of the UPS.53 Figure 1 summarizes clinical data on changes of UPS activity, expression levels of genes involved in the
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Figure 1 General connections of amyloid-beta (Abeta) and ubiquitin–proteasome system (UPS) in Alzheimer’s disease (AD). Each arrow inside the textbox indicates the performance of a corresponding incident in AD patient brains.
ubiquitin–proteasome pathway, and UPS-mediated amyloidogenic APP processing in AD patients. Corresponding regulation of these changes has been proved to attenuate AD pathology. For example, both in vitro and in vivo experiments indicate that enhancement of FBL2 function, which is disturbed in AD, is expected to be a novel therapeutic strategy for AD. Several drugs target the connection of Abeta and UPS. Resveratrol clears Abeta by a manner that implicates the proteasome.54 Treatment with apomorphine in Alzheimer mice promotes Abeta degradation by increasing the proteasome activity55 and improves memory function and AD-related pathology.56 Sulforaphane has been shown to reduce Abeta-induced cytotoxicity by enhancing proteasome activities.57 From the view of the vast present researches on various cell and animal models of AD, the future AD treatment approaches based on the connection of Abeta and the UPS may include natural and artificial medicine, projected proteins, and gene therapy.
Conclusions and Perspective Although a lot of work has been done to demonstrate the mechanisms underlying the interplay between Abeta and proteasome, some problems remain to be explored and understood. On one hand, whether Abeta causes the dysfunction of UPS or the dysfunction of UPS causes Abeta accumulation remains unclear. The two may form a vicious cycle but the issue is which event presents first in the pathogenesis of AD. More clinical data in the future might provide clues for this issue. On the other hand, Abeta is degraded by the proteasome by as-yet undetermined catalytic subunits.12 Many compartments of the UPS, such as UCHL-1 and parkin, could be attractive targets for the development of new therapeutic approaches for AD. It would be beneficial for the development of new drugs and therapies if the molecular mechanism in which UPS, Abeta, and related factors are involved in AD is further understood. We need not only notice
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some conflicting results in different experiments but also realize that the interaction of UPS, Abeta, and related factors is of great complexity. For instance, researches show that the over-expression of ubiquilin decreases PS NTF and CTF levels. Since ubiquilin proteins have been linked to the ubiquitin–proteasome pathway, it seemed possible that ubiquilin could decrease PS fragment levels by escorting the fragments to the proteasome for degradation. Surprisingly, studies showed that ubiquilin decreases PS fragments by reducing their production.51 For the sake of this complexity, mathematical methods might be necessary to explain their interplay in the future.
Acknowledgements This study was supported by the National Natural Science Foundation of China (31071512).
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repeat protein 2 decreases over Braak stages in the brains of Alzheimer’s disease patients. Neurodegener Dis. 2013;11:1–12. Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem. 2004;279:13256–64. Barrachina M, Castano E, Dalfo E, Maes T, Buesa C, Ferrer I. Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies. Neurobiol Dis. 2006;22:265–73. Guglielmotto M, Monteleone D, Boido M, Piras A, Giliberto L, Borghi R, et al. Abeta1-42-mediated down-regulation of Uch-L1 is dependent on NF-kappaB activation and impaired BACE1 lysosomal degradation. Aging Cell. 2012;11:834–44. Zhang M, Deng Y, Luo Y, Zhang S, Zou H, Cai F, et al. Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J Neurochem. 2012;120:1129–38. Hegde AN. The ubiquitin-proteasome pathway and synaptic plasticity. Learn Mem. 2010;17:314–27. Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, et al. Ubiquitin C-terminal hydrolase is an immediateearly gene essential for long-term facilitation in Aplysia. Cell. 1997;89:115–26. Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, et al. Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell. 2006;126:775–88. Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2012;2:a006270. Wang R, Ying Z, Zhao J, Zhang Y, Wang R, Lu H, et al. Lys(203) and Lys(382) are essential for the proteasomal degradation of BACE1. Curr Alzheimer Res. 2012;9:606–15. Gong B, Chen F, Pan Y, Arrieta-Cruz I, Yoshida Y, Haroutunian V, et al. SCFFbx2-E3-ligase-mediated degrada-
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tion of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. Aging Cell. 2010;9:1018–31. He G, Qing H, Tong Y, Cai F, Ishiura S, Song W. Degradation of nicastrin involves both proteasome and lysosome. J Neurochem. 2007;101:982–92. Viswanathan J, Haapasalo A, Bottcher C, Miettinen R, Kurkinen KM, Lu A, et al. Alzheimer’s disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome formation. Traffic. 2011;12:330–48. Haapasalo A, Viswanathan J, Kurkinen KM, Bertram L, Soininen H, Dantuma NP, et al. Involvement of ubiquilin-1 transcript variants in protein degradation and accumulation. Commun Integr Biol. 2011;4:428–32. Lee JE, Jeon IS, Han NE, Song HJ, Kim EG, Choi JW, et al. Ubiquilin 1 interacts with Orai1 to regulate calcium mobilization. Mol Cells. 2013;35:41–6. Massey LK, Mah AL, Monteiro MJ. Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Biochem J. 2005;391:513–25. He G, Qing H, Cai F, Kwok C, Xu H, Yu G, et al. Ubiquitinproteasome pathway mediates degradation of APH-1. J Neurochem. 2006;99:1403–12. Layfield R, Lowe J, Bedford L. The ubiquitin-proteasome system and neurodegenerative disorders. Essays Biochem. 2005;41:157–71. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem. 2005;280:37377–82. Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, et al. Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation. Ann Neurol. 2011;69:248–56. Ohyagi Y. [A drug targeting intracellular amyloid-beta and oxidative stress: Apomorphine]. Rinsho Shinkeigaku. 2011;51:884–7. Park HM, Kim JA, Kwak MK. Protection against amyloid beta cytotoxicity by sulforaphane: role of the proteasome. Arch Pharm Res. 2009;32:109–15.
Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease Liang Hong1, Han-Chang Huang1,2, Zhao-Feng Jiang1,2 1
Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, China, College of Arts and Science, Beijing Union University, China
2
Amyloid-beta (Abeta) peptide is the original causative factor of Alzheimer’s disease (AD) according to the amyloid cascade hypothesis. The ubiquitin–proteasome system (UPS), the major intracellular protein quality control system in eukaryotic cells, is related to AD pathogenesis. There is growing evidence showing that there is a tight relationship between Abeta and UPS and this relationship plays an important role in AD pathogenesis. This article reviews the relationship between Abeta and the UPS in terms of the following three aspects: the interaction of the two factors, the ubiquitinating process of Abeta, and impact of dysfunctional UPS on Abeta production. The impairment in the UPS in AD could affect the degradation of Abeta and lead to an abnormal accumulation of Abeta. At the same time, Abeta inhibits the proteasomal activity and subsequently leads to impairment of multivesicular bodies (MVB) sorting pathway, forming an interacting relationship between Abeta and UPS. Mutant ubiquitin (Ub) and ubiquitin-like (UBL) ubiquilin-1 are related to Abeta accumulation. Meanwhile E2 conjugating enzymes, E3 ligases, and de-ubiquitinating enzymes, all of which function in the ubiquitination process, play a pivotal role in the proteasomal degradation of Abeta. Ubiquitin–proteasome system has an immense impact on the amyloidogenic pathway of amyloid precursor protein (APP) processing that generates Abeta. Upregulation in proteasomal degradation of BACE1 and components of gamma-secretase leads to decreased Abeta accumulation. A deep look into the mechanism underlying the interplay between Abeta and UPS may provide alternative therapeutic targets and lead to new drugs and therapies. Keywords: Alzheimer’s disease, Amyloid-beta, Degradation, Proteasome, Ubiquitin
Introduction Amyloid-beta (Abeta) and Alzheimer’s disease (AD) A quarter of a century of research on Abeta has produced a wealth of evidence that its accumulation in brain regions serving memory and cognition contributes strongly to the development of AD.1 The amyloid cascade hypothesis, a well known hypothesis describing the pathogenesis of AD, suggests that Abeta accumulation is the earliest pathological change in AD. Amyloid-beta is the central molecule in the pathogenesis of this disease. Recent studies further suggest that intracellular Abeta accumulation plays an important role in AD. Intracellular Abeta42 accumulation occurs in the pyramidal neurons of the hippocampus and entorhinal cortex long before the emergence of Abeta plaques and paired helical filaments in the brains of AD patients.2 So, intracellular Abeta may be even Correspondence to: Zhao-Feng Jiang, Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, 197# Beitucheng West Road, Haidian District, Beijing 100191, China. Email: [email protected]
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more important than extracellular Abeta, and intraneuronal Abeta represents an alternative therapeutic target. Growing evidence shows that deficiency of the Abeta clearance may be the predominant cause of late-onset AD, which accounts for the largest percentage of AD cases. Now that intracellular Abeta is the most important form of Abeta, degradation of Abeta by intracellular pathway shall be of special importance to the pathogenesis of AD. Thus, the ubiquitin– proteasome system (UPS), as the main intracellular proteolytic pathway in eukaryotic cells, has been paid extensive attention.
Ubiquitin–proteasome system and AD Ubiquitin–proteasome system, the major protein quality control system in eukaryotic cells, degrades misfolded or other abnormally modified proteins. Most proteins designated for destruction by UPS are first tagged by a polyubiquitin chain. This ubiquitination process is ATP-dependent and occurs in a process containing three steps. First, ubiquitin (Ub) is
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activated by an E1 ubiquitin-activating enzyme; second, activated Ub binds to an E2 conjugating enzyme; and finally the Ub moiety binds to a lysine residue within the targeted protein via an E3 ligase. The polyubiquitinated substrates are then recognized, unfolded, and degraded at the 26S proteasome.3 The 26S proteasome is a multi-subunit complex composed of a central 20S catalytic core particle (20S proteasome) and one or two 19S regulatory particles. The 20S proteasome has a cylindrical structure composed of two outer alpha-rings and two inner beta-rings. Each alpha-ring is composed of seven alpha-subunits and each beta-ring is composed of seven betasubunits.4 The two outer rings close the interior of the barrel shaped complex, whereas the inner two rings consist beta-subunits including three subunits with catalytic activity. These three active subunits, which are referred to as beta1, beta2, and beta5, have caspase-like activity that cleaves substrates behind acidic residues, trypsin-like activity that cleaves substrates after basic residues, and chymotrypsin-like activity that cleaves substrates behind hydrophobic residues, respectively.5 A wealth of evidence shows that perturbation in the UPS plays a causative role in AD. The activity of proteasome is significantly decreased in the hippocampus, parahippocampal, and middle temporal gyri, and the inferior parietal lobule of Alzheimer’s patients.6 What is more, defective proteolysis may cause the synaptic dysfunction observed early in AD since protein degradation regulated via the ubiquitin proteasome system plays a critical role in synaptic plasticity.7 Besides Abeta accumulation, the perturbation of UPS correlates with other AD characteristics such as tau hyper phosphorylation and autophagy, making its role in the pathogenesis of AD very important. The biochemical and morphologic research done by Tai et al. on the location of tau in control and AD cortices demonstrates that in AD tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals and that the accumulation of these hyperphosphorylated tau oligomers is associated with the increase of ubiquitinated substrates and proteasome components. These results suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that damages synapses in AD.8 According to the study by Cecarini et al., the over-expression of the amyloid precursor protein (APP) AD-linked mutant isoform in human SH-SY5Y neuroblastoma cells correlates with a remodeled pattern of protein degradation with marked inhibition of proteasome activities and impairment in the autophagic flux.9 Although some proteins can be degraded by 20S proteasome in a way independent of ATP and ubiquitin,10 the degradation of Abeta requires ATP
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and the ubiquitination process. So, elucidating the relationship between Abeta and UPS, two most crucial factors in AD, is of great importance to the understanding of the pathogenesis of this common and severe neurodegenerative disorder and to the searching of novel pharmacological targets for AD treatment. Here we review the current knowledge of the relationship between Abeta and UPS in terms of three aspects: (1) the interplay between Abeta and UPS; (2) the impact the proteins involved in the process of ubiquitination, including ubiquitin-like (UBL) proteins and ubiquitinating enzymes, have on Abeta accumulation and the reverse effect Abeta could have on them; and (3) the relationship between UPS and Abeta production.
Interplay between Abeta and UPS The relationship between Abeta and proteasome has been paid great attention since the detection of Ub in senile plaques by Perry et al. in 1987.11 It was once assumed that proteasome might play no physiologic role in Abeta degradation since the proteasome is localized to the cytosol and Abeta is produced in lumenal compartments. However, some later reported experimental evidence suggests that Abeta42 can diffuse passively from the lumen of the endoplasmic reticulum (ER) into the cytosol, where it is degraded by the proteasome and insulin degrading enzyme (IDE).12 It turns out that UPS degrades Abeta and is at the same time effected by Abeta. There is a doubleway relationship between Abeta and UPS as described below.
Impact of UPS on Abeta Ubiquitin–proteasome system degrades Abeta and has immense effect on Abeta toxicity. In a research using primary cultures of cortical neurons and astrocytes, when the proteolytic activity of the 26S proteasome was inhibited with lactacystin, there was a marked decrease in Abeta42 degradation. This suggests that Abeta, in both astrocytes and neurons, could be a possible substrate of this enzymatic complex.13 Alterations in the Ub-proteasome pathway could affect the degradation of Abeta, leading to an abnormal Abeta accumulation.13 Thus, the formation of amyloid plaques in AD patients could be the product of ubiquitin-mediated protein degradation defects.
Impact of Abeta on UPS Amyloid-beta inhibits the proteolytic activities of the 26S proteasome.14 It is found that Abeta25–35 and Abeta42 produce a significant increase in Ub-protein conjugates and in the expression of the Ub-activating enzyme E1 in neurons.13 Intraneuronal accumulation of Ub-protein conjugates is a pathological feature of AD. It is proposed that the accumulation of ubiquitinated species in AD is a result of the inhibition of
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proteasome activity induced by Abeta peptides.15 Once, it was proposed that Abeta40 peptides localize inside the 20S subunit along the active proteolytic site and inhibit the beta5 chymotrypsin-like activity of the proteasome.16 However, a recent research shows that aggregated forms of Abeta42 are competitive substrates for the chymotrypsin-like activity of the human 20S proteasome. Hence the impairment of proteasomal function induced by Abeta may arise from the competition of natural proteasomal substrates with increasing concentrations of toxic oligomeric Abeta peptides within the cells of patients with AD.15 Inhibition of UPS by intraneuronal Abeta42 causes such consequences as the impairment of multivesicular bodies (MVB) sorting pathway.14 Since MVBs are described as important vesicles in retrograde transport, appearing to carry substance from neuronal terminals to the cell body for signaling and/or degradation in lysosomes, their impairment might provide insight into Abeta toxicity on neuronal system function.
Amyloid-beta and Ubiquitination Mutant Ub and ubiquilin A frameshift mutant of the Ub protein, UBB(z1), which accumulates in an age-dependent manner as a result of molecular misreading, contributes to neuropathology in AD. The UBB(z1) protein has been found in the brains of AD patients.17 Proteomic profile analysis shows that in UBB(z1) transgenic mice, protein changes in the brain are remarkably similar to that in the human AD brain.18 UBB(z1) ’caps’ unanchored (that is, not linked to any substrates) polyubiquitin chains, which then act as dominant inhibitors of the 26S proteasome.19 It is reasonable to presume that this inhibition of 26S proteasome would affect degradation of Abeta, leading to abnormal Abeta accumulation. Surprisingly, in the research of van Tijn et al.20, however, a significant decrease in Abeta deposition and soluble Abeta42 was observed in APPPS1/UBB(z1) transgenic mice compared with in APPPS1 mice at 6 months of age. In other words, UBB(z1) decreases Abeta plaque formation in this transgenic mouse model of AD. The molecular mechanism underlying this decrease in Abeta deposition in APPPS1/UBB(z1) mice remains to be studied. In addition, the interaction between E2-25K/Hip-2 and UBB(z1) may be critical for the synthesis and accumulation of UBB(z1)-anchored polyubiquitin, which results in proteasomal inhibition and death of the neurons.21 Single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD. Its protein product, ubiquilin-1, functions as a molecular chaperone for APP and leads to Abeta accumulation. Ubiquilin proteins are UBL proteins. They belong to
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the family of UBL–ubiquitin-associated (UBL–UBA) proteins which are implicated in the regulation of the ubiquitin-dependent proteasomal degradation of cellular proteins.22 Protein levels of ubiquilin-1 are decreased in the brains of AD patients.23,24 It was found recently that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by mediating non-degradative ubiquitination on a single lysine residue in the cytosolic domain of APP.25
Ubiquitination enzymes The critical factors modulating both Abeta neurotoxicity and UPS in AD include several ubiquitination enzymes, such as E2-25K, HRD1, Parkin and UCHL1. A lot of findings about these critical molecules have been reported recently. (i) E2-25K. An unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2 is reported as a mediator of Abeta toxicity and is upregulated in AD.6 E2– 25K is an unusual member of the E2 conjugating enzyme family in that it is competent to catalyze Ub chain extension independent of E3 ligases.21 It functions upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta42 toxicity.6 It contains a UBA domain that is unique to human E2 conjugating enzymes. Ubiquitin-associated domains appear to be generally involved in interactions with ubiquitin. Although evidence suggests that the E2–25K UBA domain is important for polyubiquitylation activity, its precise function is currently unclear. A chimeric protein in which the UBA domain of E2–25K was fused to the E2 domain of yeast UBC4 showed no polyubiquitin synthetic activity, suggesting that polyubiquitylation by E2–25K is dependent on the relative conformations of the E2 and UBA domains and their specific interactions with each other.21 Interestingly, it was reported that an active site mutation, C92S or S86Y, or deletion of the UBA domain of E2– 25K eliminated Abeta neurotoxicity.26 It was also proposed that UBB(z1) interacts with the UBA E2–25K domain and participates in the polyubiquitylation process, producing the UBB(z1)-anchored polyUb chains. However, the details of the mechanism are not yet known.21 (ii) E3 ligases. The E3 Ub protein ligases play a pivotal role in the ubiquitination reaction because they mainly determine substrate specificity of the Ub conjugation reaction and are tethers that connect ubiquitin, substrate proteins, and the 26S proteasome. The relationship between E3 ligases and Abeta has been extensively studied recently. E3 ligases include parkin, HRD1, UCHL-1, etc. UCHL-1 also functions as a de-ubiquitinating enzyme. Parkin solubility is decreased in AD cortex. Parkin co-localization with intraneuronal Abeta42 is also detected in the hippocampus and cortex of AD patients.27 Incubation of Abeta42 cell lysates with ubiquitin, in the presence of parkin, results in the
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generation of Abeta–Ub complexes.28 In a research using SH-SY5Y and primary neuronal cells, wildtype parkin reverses intracellular Abeta accumulation and its negative effects on proteasome function.29 Accordingly, in a triple transgenic AD mouse model,30 it was found that injected lentiviral parkin ubiquitinates intracellular Abeta in vivo and that parkin expression decreases intracellular Abeta levels and extracellular plaque deposition. Taken together, parkin can ubiquitinate and clear Abeta and may be an alternative therapeutic target to reduce Abeta levels and to enhance clearance of Abeta-induced defects in AD. However, adverse results were also reported. Parkin null cortical neuronal/glial cultures are more resistant to Abeta42 toxicity than wild type,31 suggesting that parkin suppression may not be a risk factor for dementia of AD type. HRD1 is another E3 ligase. The levels of HRD1 are significantly decreased in the cerebral cortex of AD patients32 and are negatively correlated with Abeta production levels. A recent study investigated the protein levels of HRD1 and SEL1L in the NP-40 detergent-insoluble fraction of the controls and AD brains as well as correlation between HRD1 and Abeta. The results suggest that the decrease in HRD1 levels in AD is a result of its insolubilization, which may be involved in Abeta generation.33 Insolubilization of HRD1 protein causes dysfunction of HRD1, and this dysfunction results in increased Abeta levels. It is also reported that HRD1 promotes APP ubiquitination and degradation, resulting in decreased generation of Abeta.32 Unlike other E3 ligases, synoviolin upregulates Abeta production. The reason may be that it regulates the assembly of the gamma-secretase complex via the degradation of Rer1.34 The expression levels of F-box and leucine rich repeat protein2 (FBL2), a component of the SCF (Skp1–Cullin1–F-box protein) E3 Ub ligase complex, are decreased in the brains of AD patients.35,36 Both in vitro and in vivo experiments indicate that enhancement of FBL2 function, which could facilitate reduction of intraneuronal Abeta, is expected to be a novel therapeutic strategy for AD.2 The mechanism underlying the therapeutic effect of FBL2 may be that FBL2 regulates APP metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis.2 (iii) UCHL-1. Ubiquitin C-terminal hydrolase-1 (UCHL-1), an E3 ligase that is expressed mainly in neurons, also functions as a de-ubiquitinating enzyme. It stabilizes mono-ubiquitinated proteins in the meantime. UCHL-1 is downregulated in AD.37 In addition, down-regulation of both UCHL-1 mRNA and UCHL-1 protein is detected in the cerebral cortex in common forms of dementia with Lewy bodies (DLB) with accompanying AD changes.38 It is observed that the low
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protein levels of UCHL-1 are associated with high protein levels of BACE1 in sporadic AD brains. Concordant with this fact, a research using different cellular models such as neuroblastoma SH-SY5Y and NT(2) neuronal cells shows that Abeta42 treatment downregulates UCHL-1 and this down-regulation is dependent on NF-kappaB activation and on impaired BACE1 lysosomal degradation.39 Ubiquitin C-terminal hydrolase-1 accelerates BACE1 degradation and affects APP processing and Abeta production.40 In conclusion, potentiation of UCHL-1 might be able to reduce the levels of BACE1 and Abeta in brain, and UCHL-1 may be a novel target for AD drug development.
It is commonly proposed that among all the ubiquitination enzymes, E3s may be the favorite potential therapeutic targets because they mainly determine substrate specificity. However, technically, the high specificity of the Ub conjugation to a certain substrate is achieved through a combinatorial coding by E1s, E2s, and E3s.41 It would be better if drugs and therapies could target the combinatorial coding for Abeta ubiquitination. UCHL-1 is an attractive drug target for AD, because besides reducing Abeta production, UCHL-1 also plays an essential role in synaptic plasticity.42 It is showed that treatment with exogenous UCHL-1 can reverse the synaptic dysfunction in hippocampal slices from APP/PSEN1 mice or synaptic plasticity impairment in hippocampal slices from normal mice caused by treatment with oligomeric Abeta.43
Ubiquitin–Proteasome System and Abeta Production Abeta is derived by sequential proteolytic processing from a large trans-membrane protein, APP. Betaand gamma-secretase liberate by sequential cleavage the neurotoxic Abeta-peptide, whereas alpha-secretase prevents its generation by cleaving within the middle of the amyloid domain.44 Here we focus on the two secretases in the amyloidogenic processing pathway to elucidate the relationship between UPS and Abeta production.
Ubiquitin–proteasome system and betasecretase Lys203 and Lys382 are essential for the proteasomal degradation of beta-secretase (BACE1).45 This degradation of BACE1 is accelerated by UCHL-1.40 Furthermore, Fbx2 is a neuron-specific F-box protein that binds the Skp1 domain of the SCF (Skp1–Cullin1–Fbox protein) to E3 Ub ligase, forming SCFFbx2–E3 ligase complex. SCFFbx2–E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and enzymatic activity,
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coincidentally reducing Abeta levels and rescuing synaptic deficits.46
Ubiquitin–proteasome system and gammasecretase The critical components of the gamma-secretase complex include nicastrin (NCT), presenilin (PS), presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1). All of these components are degraded by the UPS.47,48 Presenilin is one of the key players in AD pathogenesis. Two homologous proteins, presenilins 1 and 2 (PS1 and PS2) are encoded by chromosomes 14 and 1, respectively. Presenilin proteins are endoproteolytically cleaved into two main fragments: the NTF (PS N-terminal fragment) and the CTF (PS Cterminal fragment). The two fragments are believed to constitute the core catalytic enzyme activity of gamma-secretase. Originally identified as a PS-interacting protein, ubiquilin is an important factor in regulating PS biogenesis and metabolism. High levels of ubiquilin might reduce gamma-secretase activity by decreasing the formation of PS fragments. It is showed that specific transcript variants of ubiquilin-1, which are genetically and functionally associated to AD, regulate proteasomal and aggresomal targeting of PS1.49 The UBL and UBA domains of ubiquilin-1 are involved in the degradation of PS.50 Ubiquilin-1 is also known to co-localize and interact with PS2 at least partially via its UBA domain.48 In addition, proteasome might function as the presenilinase that is responsible for PS endoproteolysis.51 High levels of ubiquilin decrease PEN-2 and NCT levels. What is more, inhibition of proteasomal APH1 degradation facilitated gamma-secretase cleavage of APP to generate Abeta.52 Apart from BACE1 and various components of gamma-secretase, a lot of other proteins involved in the APP metabolism, including full-length and Cterminal fragments of APP generated by beta-secretase (CTFbeta), are ubiquitinated and degraded in a proteasome-dependent manner. Many components of UPS regulate APP metabolism, showing a tight relationship between UPS and Abeta production.
Clinical Data, Drug Application, and Therapies on the Connection between Abeta and UPS The connection of Abeta and proteasome has been paid attention since the detection of Ub in senile plaques by Perry et al. in 1987.11 The disease-related proteins that form aggregates in other human neurodegenerative disorders are also found conjugated with ubiquitin, suggesting a common link between pathological protein-aggregation events in the nervous system and dysfunction of the UPS.53 Figure 1 summarizes clinical data on changes of UPS activity, expression levels of genes involved in the
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Figure 1 General connections of amyloid-beta (Abeta) and ubiquitin–proteasome system (UPS) in Alzheimer’s disease (AD). Each arrow inside the textbox indicates the performance of a corresponding incident in AD patient brains.
ubiquitin–proteasome pathway, and UPS-mediated amyloidogenic APP processing in AD patients. Corresponding regulation of these changes has been proved to attenuate AD pathology. For example, both in vitro and in vivo experiments indicate that enhancement of FBL2 function, which is disturbed in AD, is expected to be a novel therapeutic strategy for AD. Several drugs target the connection of Abeta and UPS. Resveratrol clears Abeta by a manner that implicates the proteasome.54 Treatment with apomorphine in Alzheimer mice promotes Abeta degradation by increasing the proteasome activity55 and improves memory function and AD-related pathology.56 Sulforaphane has been shown to reduce Abeta-induced cytotoxicity by enhancing proteasome activities.57 From the view of the vast present researches on various cell and animal models of AD, the future AD treatment approaches based on the connection of Abeta and the UPS may include natural and artificial medicine, projected proteins, and gene therapy.
Conclusions and Perspective Although a lot of work has been done to demonstrate the mechanisms underlying the interplay between Abeta and proteasome, some problems remain to be explored and understood. On one hand, whether Abeta causes the dysfunction of UPS or the dysfunction of UPS causes Abeta accumulation remains unclear. The two may form a vicious cycle but the issue is which event presents first in the pathogenesis of AD. More clinical data in the future might provide clues for this issue. On the other hand, Abeta is degraded by the proteasome by as-yet undetermined catalytic subunits.12 Many compartments of the UPS, such as UCHL-1 and parkin, could be attractive targets for the development of new therapeutic approaches for AD. It would be beneficial for the development of new drugs and therapies if the molecular mechanism in which UPS, Abeta, and related factors are involved in AD is further understood. We need not only notice
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some conflicting results in different experiments but also realize that the interaction of UPS, Abeta, and related factors is of great complexity. For instance, researches show that the over-expression of ubiquilin decreases PS NTF and CTF levels. Since ubiquilin proteins have been linked to the ubiquitin–proteasome pathway, it seemed possible that ubiquilin could decrease PS fragment levels by escorting the fragments to the proteasome for degradation. Surprisingly, studies showed that ubiquilin decreases PS fragments by reducing their production.51 For the sake of this complexity, mathematical methods might be necessary to explain their interplay in the future.
Acknowledgements This study was supported by the National Natural Science Foundation of China (31071512).
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