Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2019 / Article
Special Issue

Oxidative Stress and Mitochondrial Damage in Neurodegenerative Diseases: From Molecular Mechanisms to Targeted Therapies

View this Special Issue

Review Article | Open Access

Volume 2019 |Article ID 5410657 | 9 pages | https://doi.org/10.1155/2019/5410657

Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator

Academic Editor: Sander Bekeschus
Received05 Apr 2019
Accepted02 Jun 2019
Published22 Jul 2019

Abstract

Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α2M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). α2M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example, α2M can stabilise and facilitate the clearance of the Alzheimer’s disease-associated amyloid beta (Aβ) peptide. Additionally, α2M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions of α2M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the native α2M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation of α2M and the possible implications of this in neuroinflammation and neurodegeneration.

1. Structure and Function

α2M is a secreted protein that is present at 1.5–2 mg mL−1 and 1.0–3.6 μg mL−1 in human blood plasma and cerebral spinal fluid, respectively [1, 2]. The cage-like structure of α2M (720 kDa) is formed by the assembly of four 180 kDa subunits into two disulfide-linked dimers, which noncovalently associate to complete the tetrameric quaternary structure of the protein [3]. A bait region that contains a large number of protease cleavage sites is responsible for the incredibly diverse range of proteases that interact with α2M [4]. Cleavage of the α2M bait region, which is in close physical proximity to a reactive thioester bond, results in covalent trapping of proteases within a steric cage [5]. This process involves a substantial conformational change that generates a compact tetrameric form [6] and reveals the binding site for the low-density lipoprotein receptor-related protein-1 (LRP1) [7, 8] (Figure 1(a)). For the purpose of this review, the compact tetrameric protease-bound form of α2M is referred to as transformed α2M. Transformed α2M (covalently bound to up to two protease molecules) is rapidly cleared from the circulation via LRP1-facilitated endocytosis (Figure 1(a)). As such, α2M can efficiently inhibit a myriad of extracellular processes that are dependent on proteolysis.

Consistent with having an ancient origin in innate immunity, α2M is a promiscuous protein that noncovalently binds to a diverse range of nonprotease ligands including cytokines [9, 10], growth factors [914], apolipoproteins [15], and misfolded proteins [1620]. Many noncovalent ligands of α2M including the Alzheimer’s disease-associated Aβ peptide [21], neurotrophins [14], and tumour necrosis factor-alpha (TNF-α) preferentially bind to transformed α2M which is generated following the reaction of native α2M with a protease or with small nucleophilic compounds that also target the α2M thioester bond [6]. In these cases, it is proposed that transformed α2M acts to limit the activities of noncovalently bound ligands by facilitating their disposal via LRP1 [10, 22] (Figure 1(a)). On the other hand, α2M can control signalling pathways via alternative mechanisms. For example, the binding of α2M to phosphorylated insulin-like growth factor binding protein-1 abrogates its inhibitory effects on insulin-like growth factor-1 (IGF-1); therefore, in some scenarios, α2M can potentiate growth factor signalling [13]. Another example whereby α2M is reported to potentiate growth factor signalling involves the pronerve growth factor (pro-NGF), which induces the expression of TNF-α via stimulating the neurotrophin receptor p75 [11]. Although α2M potentiates pro-NGF signalling in vitro, α2M is reported to inhibit the activity of mature NGF by binding either to NGF or to Trk receptors [12, 23, 24].

The accumulation of misfolded proteins is inherently deleterious to living organisms and underlies the pathology of many human diseases including Alzheimer’s disease, Parkinson’s disease, and motor neuron disease. α2M is one of a small number of secreted proteins that are known to possess holdase-type chaperone activity, which is the ability to stabilise misfolded proteins and prevent their aberrant aggregation [1620, 25]. The chaperone function of α2M has been demonstrated in vitro using a broad range of misfolded clients including denatured globular proteins and aggregation prone, intrinsically disordered substrates (e.g., Aβ peptide and Parkinson’s disease-associated alpha-synuclein). Furthermore, it has been shown that α2M preferentially binds several plasma proteins in situ following experimentally-induced shear stress which causes plasma protein aggregation [18, 19]. The likely fate for complexes formed between native α2M and misfolded proteins is clearance via LRP1 following interaction with a protease [16, 22, 2527] (Figure 1(a)). However, protease-transformed α2M can also inhibit Aβ aggregation via degrading the peptide because trapped proteases remain active following covalent binding to α2M [18, 19]. The neuroprotective activity of α2M against the toxicity induced by misfolded proteins has been demonstrated using several in vitro models [17, 25, 27, 28] and has also been demonstrated in rats directly injected with toxic Aβ oligomers [29]. Taken together, the results of these studies support the conclusion that the functions of α2M are broadly important to extracellular proteostasis.

2. α2M and Neurodegenerative Diseases

Interest in the role of α2M in Alzheimer’s disease spans several decades. In part, this stems from early reports that polymorphisms in α2M are associated with increased risk of Alzheimer’s disease in some populations [3036]. However, opposing results have also been presented [37, 38], and more recent genome-wide association studies have not found any association [39]. It has recently been reported that serum α2M is elevated in men with preclinical Alzheimer’s disease, which potentially represents a general response to neuronal injury [40]. The significance of elevated levels of α2M is hard to determine, because aside from influencing Aβ aggregation and clearance, there are many other relevant biological processes that α2M potentially influences. For example, apolipoprotein E (ApoE) is an endogenous ligand of α2M in blood plasma, and the binding of α2M to the ε4 isoform (the strongest known genetic risk factor for Alzheimer’s disease) is much less compared to the binding of α2M to the ε2 and ε3 ApoE isoforms [15]. The functional importance of this interaction has yet to be solved.

There is strong evidence that native α2M can inhibit the aggregation and toxicity of Aβ peptide (the major constituent of extracellular plaques in Alzheimer’s disease). Furthermore, the widely documented ability of α2M to facilitate the clearance of the Aβ peptide is central to its neuroprotective action [17, 25, 2729]. α2M is found colocalised with the Aβ peptide in the brain in Alzheimer’s disease [41, 42], which supports the idea that the LRP1-mediated clearance of α2M-Aβ complexes is impaired or overwhelmed. Similar to α2M, there are conflicting reports regarding an association between polymorphisms in LRP1 and the risk of Alzheimer’s disease (reviewed in [43]). Given that the accumulation of the Aβ peptide in the brain in Alzheimer’s disease appears to be the result of a defect in clearance, rather than elevated production of the peptide [44], it is important to understand the contribution of α2M to the clearance of the Aβ peptide in greater detail.

Roles for α2M in preventing or promoting neurodegeneration independent of Alzheimer’s disease are less clear. Nevertheless, α2M is reported to bind to a broad range of misfolded proteins including the infectious prion protein that is responsible for transmissible spongiform encephalopathies [45] and α-synuclein, the major constituent of misfolded protein deposits in Parkinson’s disease [17]. In the case of the prion protein, it has been reported that binding to α2M in vitro facilitates the conformational change in the prion protein that is responsible for its infectious characteristics [45]. On the other hand, similar to the protective effect of α2M on Aβ toxicity, the binding of α2M to α-synuclein is cytoprotective [17]. α2M also potentially inhibits neurodegeneration by influencing the activity of neurotrophins such as NGF and pro-NGF or by inhibiting the activity of neurotrophin receptors directly [12, 23, 24]. The latter could have relevance in a range of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease in which aberrant neurotrophin signalling is implicated [46]. Moreover, the ability of α2M to bind to proinflammatory mediators such as TNF-α, IL-6, and IL-1β [4749] supports the idea that α2M has generalised importance in controlling inflammatory processes including in the central nervous system.

3. Hypochlorite, a Novel Regulator of α2M Functions

Hypochlorite (OCl-) is a powerful oxidant that is produced by the action of the enzyme myeloperoxidase during inflammation. Myeloperoxidase is not detected in the brains of healthy individuals; however, in neuroinflammatory disorders, myeloperoxidase is generated by activated microglia and astrocytes [5054]. Infiltrating monocytes/macrophages and neutrophils can also contribute to myeloperoxidase production in the brain [50, 55]. Although the reasons for this are unclear, myeloperoxidase-immunoreactivity is also detected in neurons in Alzheimer’s disease [50, 51]. Interestingly, in a mouse model of Parkinson’s disease, ablation of the myeloperoxidase gene is protective, which supports the conclusion that myeloperoxidase is a major contributor to the oxidative damage generated by pathological neuroinflammatory processes [56].

Hypochlorite production is primarily considered important for defence against invading microbes [57]. The effectiveness of hypochlorite as a microbicidal agent is linked to the potency with which hypochlorite damages proteins, inducing their misfolding [58, 59]. Given that reaction with hypochlorite is not specific to molecules of microbial origin, the generation of hypochlorite is associated with collateral damage to the host organism. As a result of aberrant inflammatory activity, hypochlorite-modified proteins accumulate in a large number of pathologies including Alzheimer’s disease [51], atherosclerosis [60], kidney disease [61], rheumatoid arthritis [52] and in experimental animal models of Parkinson’s disease [56] and multiple sclerosis [62]. Hypochlorite-induced modification can directly cause proteins to adopt immunostimulatory and cytotoxic properties. For example, hypochlorite-induced modification of apolipoprotein B-100, the major protein component of low-density lipoprotein particles, promotes macrophage foam cell formation and triggers platelet aggregation [63]. Additionally, hypochlorite-modified albumin is known to promote proinflammatory signalling [64], endothelial cell dysfunction [65], and apoptosis [66].

It is well-known that antioxidants are the first line of defence that protects the host from excessive oxidative damage during inflammation. However, evidence has emerged that supports the conclusion that specialised hypochlorite-inducible systems are also important. Around a decade ago, it was demonstrated that the activity of the bacterial chaperone Hsp33 is directly enhanced following reaction with hypochlorite and the chaperone activity of hypochlorite-modified Hsp33 protects bacteria from hypochlorite-induced death [59]. More recently, it has been demonstrated that reaction with hypochlorite induces the dissociation of the native α2M tetramer into dimers that have dramatically enhanced chaperone activity compared to the native α2M tetramer [25] (Figure 1(b)). The mechanism responsible for the enhanced chaperone activity of hypochlorite-modified α2M dimers involves the exposure of the normally buried hydrophobic surfaces that are situated at the interface of noncovalently-associated dimers in the native α2M tetramer [25] (Figure 2). It has been reported that methionine oxidation is largely responsible for the hypochlorite-induced dissociation of α2M into dimers [67]; however, aromatic amino acids are also modified by physiologically relevant levels of hypochlorite [25, 68, 69]. The results of biophysical analyses show that physiologically-relevant levels of hypochlorite also alter the secondary structure of α2M subunits [25, 68]. Precisely how hypochlorite-induced modification of the secondary structure of α2M influences its functions is not known.

During inflammation, extracellular protease activity and the generation of hypochlorite are both elevated; therefore, it is plausible that protease-transformed α2M and hypochlorite-induced α2M dimers are concomitantly generated in vivo. Hypochlorite-induced modification of native α2M exposes its LRP1 binding sites ([25, 70]); therefore, during inflammation, α2M and its cargoes are potentially cleared via two distinct mechanisms involving LRP1 (Figure 1(a): protease-transformed α2M and Figure 1(b): hypochlorite-induced α2M dimers). The dissociation constant for the binding of hypochlorite-modified α2M to LRP1 is reportedly ~0.7 nM [70] compared to 40 pM—2 nM for the transformed α2M [71]. Unlike native α2M, reaction with hypochlorite does not induce transformed α2M (generated using methylamine) to dissociate into dimers, and the resultant hypochlorite-induced damage reduces the binding of transformed α2M to LRP1 [70]. Therefore, during inflammation, the generation of hypochlorite potentially enhances the delivery of hypochlorite-modified α2M dimers that are generated from the native α2M tetramer to LRP1, while impeding the delivery of transformed α2M to the same receptor.

Although the chaperone activity of native α2M is enhanced following hypochlorite-induced modification, similar levels of hypochlorite-induced modification abolish the protease trapping function of α2M [72, 73]. Collectively, the evidence suggests that reaction with hypochlorite is a rapid switch that regulates the activities of α2M during inflammation. Supporting this idea, it has been reported that hypochlorite-induced modification of α2M also regulates its binding to cytokines and growth factors in a manner that increases its binding to TNF-α, IL-2, and IL-6 (involving preferential binding to hypochlorite-induced α2M dimers) and decreases its binding to β-NGF, PDGF-BB, TGF-β1, and TGF-β2 in vitro [74] (Figure 1(b)). Furthermore, hypochlorite-induced dissociation of α2M enhances its cytoprotective effect against TNF-α in vitro [74]. Interestingly, it has been reported that the complement system, which includes several proteins that are closely related to α2M, is also activated by reaction with hypochlorite [75, 76]. Therefore, it is tempting to speculate that hypochlorite-induced regulation is a characteristic that is shared by this family of proteins.

Studies of the hypochlorite-induced regulation of α2M are currently limited to in vitro systems; however, using the specific marker for reaction with hypochlorite 3-chlorotyrosine, it has been shown that α2M is modified by hypochlorite in synovial fluid from inflamed joints [69]. Moreover, considering that hypochlorite levels are predicted to reach the low millimolar range in tissues during inflammation [77], it is plausible that hypochlorite-modified α2M dimers are generated in biological fluids during inflammation. Of the studies reporting an association between mutation in α2M and risk of Alzheimer’s disease, one study has reported that there is a synergistic effect between polymorphisms in α2M and myeloperoxidase and an increased risk of Alzheimer’s disease [36]. The results of the latter study support the idea that the functions of these two proteins might interrelate in a way that is important to neurodegeneration. It is not currently known if any of the other identified extracellular chaperones (e.g., clusterin and haptoglobin) might also have their activities regulated by hypochlorite-induced modification, but this is an area worthy of future investigation.

4. PZP, a Dimeric α2M-like Molecule

The major structural modification induced by reaction with hypochlorite that is responsible for functionally controlling α2M is the dissociation of the native α2M tetramer into dimers. Strikingly, many mammals are capable of generating large amounts of a dimeric α2M-like protein known as pregnancy zone protein (PZP). In humans, α2M and PZP share very high sequence homology in all domains (71% amino acid identity), with the exception of the bait region [4, 78]. As a result, the ability of PZP to inhibit proteases is much more restricted compared to that of α2M. Few in vitro studies have focused on characterising the functions of PZP; however, it has been proposed that PZP contributes to regulating glycodelin-A (a paracrine mediator in early pregnancy) and TGF-β2 (important for embryonic development) [12, 7981]. Consistent with this idea, PZP is usually lowly abundant in biological fluids but is markedly upregulated in pregnancy [82]. On the other hand, glycodelin-A and TGF-β2 are also ligands for constitutively abundant α2M ([12, 7981]); therefore, the precise importance of PZP as a modulator of these signalling pathways remains unclear. Similarly, several neurotrophins are shared ligands of PZP and α2M, but the precise biological importance of these interactions is not known [12]. Pregnancy-independent expression of PZP is widely reported in diseases such as Alzheimer’s disease [83, 84], Parkinson’s disease [85], rheumatoid arthritis [86], Behcet’s syndrome [87], psoriasis [88, 89], Chagas disease [90], viral infection [91, 92], inflammatory bowel disease [93], and cancers [94, 95]. The latter observations support the idea that the upregulation of PZP could be a general stress response that is related to chronic inflammation. This limits the usefulness of PZP as a diagnostic marker; however, the results of studies of lymphoma and arthritis patients suggest that PZP levels are potentially useful for monitoring disease progression [95, 96].

The ability of native tetrameric α2M to inhibit Aβ aggregation is restricted to binding to soluble Aβ oligomers formed early during the aggregation pathway [20]. In contrast, transformed α2M and hypochlorite-modified α2M dimers bind to monomeric Aβ [21, 25], presumably via the hydrophobic binding site (centred at amino acids 1314–1365) identified by [21] (Figure 2). Intuitively, surface exposure of this site contributes to the efficiency with which hypochlorite-modified α2M dimers inhibit Aβ amyloid formation compared to native α2M [25]. Similarly, the results of recent studies show that PZP binds to the monomeric Aβ peptide and prevents the aggregation of the Aβ peptide much more efficiently than native α2M [97]. Whether or not PZP contributes to the clearance of the Aβ peptide in vivo is currently unknown; however, it has been demonstrated that PZP levels are elevated in women with presymptomatic Alzheimer’s disease and PZP is found colocalised with microglia around Aβ plaques in the brain in Alzheimer’s disease [83, 84]. Combined, these observations suggest that PZP is likely to participate in Aβ homeostasis. Whether or not the role of PZP overlaps with or is discrete from that of α2M remains to be determined.

5. Concluding Remarks

α2M is a remarkably multifunctional protein that can influence a broad range of biological processes. Direct injection of α2M into inflamed joints has been shown to have protective effects in a rodent model of osteoarthritis ([98]); however, the efficacy and safety of this as a human therapy is not yet known. An alternative α2M-based anti-inflammatory strategy involves the oral administration of proteases, which is proposed to increase levels of transformed α2M in blood plasma [99, 100]. This strategy is clearly limited by the poor bioavailability of orally administered proteases, but this problem could potentially be overcome by the identification of bioavailable small molecule modifiers of α2M function.

Growing evidence suggests that hypochlorite-induced dissociation of α2M into dimers is a rapid switch that enhances the ability of α2M to facilitate the clearance of disease-associated misfolded proteins and proinflammatory cytokines during inflammation. This is potentially a broadly important process that occurs in response to inflammation, including in neurodegenerative disorders in which neuroinflammation is known to be an early event that precedes other pathological changes (reviewed in [101]). A deeper understanding of the physiological relevance of hypochlorite-induced α2M dimers has the potential to shed much needed light on the participation of α2M in controlling inflammatory processes and extracellular protein homeostasis during neuroinflammation.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Acknowledgments

JHC is supported by an Australian Institute of Nuclear Science and Engineering (AINSE) postdoctoral award and an Australian Postgraduate Award (Commonwealth Government of Australia). This work was also supported by funding from the Australian Research Council (DP160100011 awarded to MRW), the National Health and Medical Research Council of Australia (APP1099991; awarded to ARW), and the Flinders Foundation (awarded to ARW).

References

  1. M. J. Garton, G. Keir, M. V. Lakshmi, and E. J. Thompson, “Age-related changes in cerebrospinal fluid protein concentrations,” Journal of the Neurological Sciences, vol. 104, no. 1, pp. 74–80, 1991. View at: Publisher Site | Google Scholar
  2. L. Sottrup-Jensen, “Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation,” The Journal of Biological Chemistry, vol. 264, no. 20, pp. 11539–11542, 1989. View at: Google Scholar
  3. A. Marrero, S. Duquerroy, S. Trapani et al., “The Crystal Structure of Human α2-Macroglobulin Reveals a Unique Molecular Cage,” Angewandte Chemie (International Ed. in English), vol. 51, no. 14, pp. 3340–3344, 2012. View at: Publisher Site | Google Scholar
  4. L. Sottrup-Jensen, O. Sand, L. Kristensen, and G. H. Fey, “The alpha-macroglobulin bait region. Sequence diversity and localization of cleavage sites for proteinases in five mammalian alpha-macroglobulins,” The Journal of Biological Chemistry, vol. 264, no. 27, pp. 15781–15789, 1989. View at: Google Scholar
  5. A. J. Barrett and P. M. Starkey, “The interaction of alpha 2-macroglobulin with proteinases. Characteristics and specificity of the reaction, and a hypothesis concerning its molecular mechanism,” The Biochemical Journal, vol. 133, no. 4, pp. 709–724, 1973. View at: Publisher Site | Google Scholar
  6. A. J. Barrett, M. A. Brown, and C. A. Sayers, “The electrophoretically ‘slow’ and ‘fast’ forms of the alpha 2-macroglobulin molecule,” The Biochemical Journal, vol. 181, no. 2, pp. 401–418, 1979. View at: Publisher Site | Google Scholar
  7. J. D. Ashcom, S. E. Tiller, K. Dickerson, J. L. Cravens, W. S. Argraves, and D. K. Strickland, “The human alpha 2-macroglobulin receptor: identification of a 420-kD cell surface glycoprotein specific for the activated conformation of alpha 2-macroglobulin,” The Journal of Cell Biology, vol. 110, no. 4, pp. 1041–1048, 1990. View at: Publisher Site | Google Scholar
  8. T. Kristensen, S. K. Moestrup, J. Gliemann, L. Bendtsen, O. Sand, and L. Sottrup-Jensen, “Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor,” FEBS Letters, vol. 276, no. 1-2, pp. 151–155, 1990. View at: Publisher Site | Google Scholar
  9. S. L. Gonias, A. Carmichael, J. M. Mettenburg, D. W. Roadcap, W. P. Irvin, and D. J. Webb, “Identical or overlapping sequences in the primary structure of human alpha(2)-macroglobulin are responsible for the binding of nerve growth factor-beta, platelet-derived growth factor-BB, and transforming growth factor-beta,” The Journal of Biological Chemistry, vol. 275, no. 8, pp. 5826–5831, 2000. View at: Publisher Site | Google Scholar
  10. J. LaMarre, G. K. Wollenberg, S. L. Gonias, and M. A. Hayes, “Cytokine binding and clearance properties of proteinase-activated alpha 2-macroglobulins,” Laboratory Investigation, vol. 65, no. 1, pp. 3–14, 1991. View at: Google Scholar
  11. P. F. Barcelona and H. U. Saragovi, “A pro-nerve growth factor (proNGF) and NGF binding protein, α2-macroglobulin, differentially regulates p75 and TrkA receptors and is relevant to neurodegeneration ex vivo and in vivo,” Molecular and Cellular Biology, vol. 35, no. 19, pp. 3396–3408, 2015. View at: Publisher Site | Google Scholar
  12. E. L. Skornicka, X. Shi, and P. H. Koo, “Comparative binding of biotinylated neurotrophins to alpha(2)-macroglobulin family of proteins: relationship between cytokine-binding and neuro-modulatory activities of the macroglobulins,” Journal of Neuroscience Research, vol. 67, no. 3, pp. 346–353, 2002. View at: Publisher Site | Google Scholar
  13. M. Westwood, J. D. Aplin, I. A. Collinge, A. Gill, A. White, and J. M. Gibson, “Alpha 2-macroglobulin: a new component in the insulin-like growth factor/insulin-like growth factor binding protein-1 axis,” The Journal of Biological Chemistry, vol. 276, no. 45, pp. 41668–41674, 2001. View at: Publisher Site | Google Scholar
  14. B. B. Wolf and S. L. Gonias, “Neurotrophin binding to human alpha 2-macroglobulin under apparent equilibrium conditions,” Biochemistry, vol. 33, no. 37, pp. 11270–11277, 1994. View at: Publisher Site | Google Scholar
  15. L. Krimbou, M. Tremblay, J. Davignon, and J. S. Cohn, “Association of apolipoprotein E with alpha2-macroglobulin in human plasma,” Journal of Lipid Research, vol. 39, no. 12, pp. 2373–2386, 1998. View at: Google Scholar
  16. K. French, J. J. Yerbury, and M. R. Wilson, “Protease activation of alpha2-macroglobulin modulates a chaperone-like action with broad specificity,” Biochemistry, vol. 47, no. 4, pp. 1176–1185, 2008. View at: Publisher Site | Google Scholar
  17. D. R. Whiten, D. Cox, M. H. Horrocks et al., “Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers,” Cell Reports, vol. 23, no. 12, pp. 3492–3500, 2018. View at: Publisher Site | Google Scholar
  18. A. R. Wyatt, P. Constantinescu, H. Ecroyd et al., “Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms,” FEBS Letters, vol. 587, no. 5, pp. 398–403, 2013. View at: Publisher Site | Google Scholar
  19. A. R. Wyatt, N. W. Zammit, and M. R. Wilson, “Acute phase proteins are major clients for the chaperone action of α2-macroglobulin in human plasma,” Cell Stress & Chaperones, vol. 18, no. 2, pp. 161–170, 2013. View at: Publisher Site | Google Scholar
  20. J. J. Yerbury, J. R. Kumita, S. Meehan, C. M. Dobson, and M. R. Wilson, “Alpha2-macroglobulin and haptoglobin suppress amyloid formation by interacting with prefibrillar protein species,” The Journal of Biological Chemistry, vol. 284, no. 7, pp. 4246–4254, 2009. View at: Publisher Site | Google Scholar
  21. J. M. Mettenburg, D. J. Webb, and S. L. Gonias, “Distinct binding sites in the structure of alpha 2-macroglobulin mediate the interaction with beta-amyloid peptide and growth factors,” The Journal of Biological Chemistry, vol. 277, no. 15, pp. 13338–13345, 2002. View at: Publisher Site | Google Scholar
  22. M. Narita, D. M. Holtzman, A. L. Schwartz, and G. Bu, “α2-Macroglobulin complexes with and mediates the endocytosis of β-amyloid peptide via cell surface low-density lipoprotein receptor-related protein,” Journal of Neurochemistry, vol. 69, no. 5, pp. 1904–1911, 2002. View at: Publisher Site | Google Scholar
  23. P. H. Koo and W. S. Qiu, “Monoamine-activated alpha 2-macroglobulin binds trk receptor and inhibits nerve growth factor-stimulated trk phosphorylation and signal transduction,” The Journal of Biological Chemistry, vol. 269, no. 7, pp. 5369–5376, 1994. View at: Google Scholar
  24. D. J. Liebl and P. H. Koo, “Serotonin-activated alpha 2-macroglobulin inhibits neurite outgrowth and survival of embryonic sensory and cerebral cortical neurons,” Journal of Neuroscience Research, vol. 35, no. 2, pp. 170–182, 1993. View at: Publisher Site | Google Scholar
  25. A. R. Wyatt, J. R. Kumita, R. W. Mifsud, C. A. Gooden, M. R. Wilson, and C. M. Dobson, “Hypochlorite-induced structural modifications enhance the chaperone activity of human 2-macroglobulin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 20, pp. E2081–E2090, 2014. View at: Publisher Site | Google Scholar
  26. Z. Qiu, D. K. Strickland, B. T. Hyman, and G. W. Rebeck, “Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons,” Journal of Neurochemistry, vol. 73, no. 4, pp. 1393–1398, 1999. View at: Google Scholar
  27. J. J. Yerbury and M. R. Wilson, “Extracellular chaperones modulate the effects of Alzheimer’s patient cerebrospinal fluid on Abeta(1-42) toxicity and uptake,” Cell Stress & Chaperones, vol. 15, no. 1, pp. 115–121, 2010. View at: Publisher Site | Google Scholar
  28. C. Fabrizi, R. Businaro, G. M. Lauro, and L. Fumagalli, “Role of alpha2-macroglobulin in regulating amyloid beta-protein neurotoxicity: protective or detrimental factor?” Journal of Neurochemistry, vol. 78, no. 2, pp. 406–412, 2001. View at: Publisher Site | Google Scholar
  29. R. Cascella, S. Conti, F. Tatini et al., “Extracellular chaperones prevent Aβ42-induced toxicity in rat brains,” Biochimica et Biophysica Acta, vol. 1832, no. 8, pp. 1217–1226, 2013. View at: Publisher Site | Google Scholar
  30. V. Alvarez, R. Alvarez, C. H. Lahoz et al., “Association between an alpha(2) macroglobulin DNA polymorphism and late-onset Alzheimer's disease,” Biochemical and Biophysical Research Communications, vol. 264, no. 1, pp. 48–50, 1999. View at: Publisher Site | Google Scholar
  31. D. Blacker, M. A. Wilcox, N. M. Laird et al., “Alpha-2 macroglobulin is genetically associated with Alzheimer disease,” Nature Genetics, vol. 19, no. 4, pp. 357–360, 1998. View at: Publisher Site | Google Scholar
  32. A. Liao, R. M. Nitsch, S. M. Greenberg et al., “Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer’s disease,” Human Molecular Genetics, vol. 7, no. 12, pp. 1953–1956, 1998. View at: Publisher Site | Google Scholar
  33. E. Mariani, D. Seripa, T. Ingegni et al., “Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer’s disease,” Journal of the Neurological Sciences, vol. 247, no. 2, pp. 187–191, 2006. View at: Publisher Site | Google Scholar
  34. A. J. Saunders, L. Bertram, K. Mullin et al., “Genetic association of Alzheimer’s disease with multiple polymorphisms in alpha-2-macroglobulin,” Human Molecular Genetics, vol. 12, no. 21, pp. 2765–2776, 2003. View at: Publisher Site | Google Scholar
  35. X. Xu, Y. Wang, L. Wang et al., “Meta-analyses of 8 polymorphisms associated with the risk of the Alzheimer’s disease,” PLoS One, vol. 8, no. 9, article e73129, 2013. View at: Publisher Site | Google Scholar
  36. M. Zappia, I. Manna, P. Serra et al., “Increased risk for Alzheimer disease with the interaction of MPO and A2M polymorphisms,” Archives of Neurology, vol. 61, no. 3, pp. 341–344, 2004. View at: Publisher Site | Google Scholar
  37. L. Chen, L. Baum, H. K. Ng et al., “Apolipoprotein E promoter and α2-macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer’s disease,” Neuroscience Letters, vol. 269, no. 3, pp. 173–177, 1999. View at: Publisher Site | Google Scholar
  38. F. Wavrant-DeVrièze, V. Rudrasingham, J. C. Lambert et al., “No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer’s disease,” Neuroscience Letters, vol. 262, no. 2, pp. 137–139, 1999. View at: Publisher Site | Google Scholar
  39. L. Shen and J. Jia, “An overview of genome-wide association studies in Alzheimer’s disease,” Neuroscience Bulletin, vol. 32, no. 2, pp. 183–190, 2016. View at: Publisher Site | Google Scholar
  40. V. R. Varma, Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) studies, S. Varma et al., “Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway,” Molecular Psychiatry, vol. 22, no. 1, pp. 13–23, 2017. View at: Publisher Site | Google Scholar
  41. D. R. Thal, R. Schober, and G. Birkenmeier, “The subunits of alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein, native and transformed alpha2-macroglobulin and interleukin 6 in Alzheimer’s disease,” Brain Research, vol. 777, no. 1-2, pp. 223–227, 1997. View at: Publisher Site | Google Scholar
  42. D. Van Gool, B. de Strooper, F. Van Leuven, E. Triau, and R. Dom, “α2-macroglobulin expression in neuritic-type plaques in patients with Alzheimer's disease,” Neurobiology of Aging, vol. 14, no. 3, pp. 233–237, 1993. View at: Publisher Site | Google Scholar
  43. M. Shinohara, M. Tachibana, T. Kanekiyo, and G. Bu, “Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies,” Journal of Lipid Research, vol. 58, no. 7, pp. 1267–1281, 2017. View at: Publisher Site | Google Scholar
  44. R. Deane, R. Bell, A. Sagare, and B. Zlokovic, “Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease,” CNS & Neurological Disorders Drug Targets, vol. 8, no. 1, pp. 16–30, 2009. View at: Publisher Site | Google Scholar
  45. V. Adler, E. Davidowitz, P. Tamburi, P. Rojas, and A. Grossman, “α2-Macroglobulin is a potential facilitator of prion protein transformation,” Amyloid, vol. 14, no. 1, pp. 1–10, 2007. View at: Publisher Site | Google Scholar
  46. J. Meldolesi, “Neurotrophin receptors in the pathogenesis, diagnosis and therapy of neurodegenerative diseases,” Pharmacological Research, vol. 121, pp. 129–137, 2017. View at: Publisher Site | Google Scholar
  47. W. Borth, A. Urbanski, R. Prohaska, M. Susanj, and T. A. Luger, “Binding of recombinant interleukin-1 beta to the third complement component and alpha 2-macroglobulin after activation of serum by immune complexes,” Blood, vol. 75, no. 12, pp. 2388–2395, 1990. View at: Google Scholar
  48. T. Matsuda, T. Hirano, S. Nagasawa, and T. Kishimoto, “Identification of alpha 2-macroglobulin as a carrier protein for IL-6,” The Journal of Immunology, vol. 142, no. 1, pp. 148–152, 1989. View at: Google Scholar
  49. G. K. Wollenberg, J. LaMarre, S. Rosendal, S. L. Gonias, and M. A. Hayes, “Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin,” The American Journal of Pathology, vol. 138, no. 2, pp. 265–272, 1991. View at: Google Scholar
  50. S. Gellhaar, D. Sunnemark, H. Eriksson, L. Olson, and D. Galter, “Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease,” Cell and Tissue Research, vol. 369, no. 3, pp. 445–454, 2017. View at: Publisher Site | Google Scholar
  51. P. S. Green, A. J. Mendez, J. S. Jacob et al., “Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease,” Journal of Neurochemistry, vol. 90, no. 3, pp. 724–733, 2004. View at: Publisher Site | Google Scholar
  52. L. K. Stamp, I. Khalilova, J. M. Tarr et al., “Myeloperoxidase and oxidative stress in rheumatoid arthritis,” Rheumatology, vol. 51, no. 10, pp. 1796–1803, 2012. View at: Publisher Site | Google Scholar
  53. D. L. Lefkowitz and S. S. Lefkowitz, “Microglia and myeloperoxidase: a deadly partnership in neurodegenerative disease,” Free Radical Biology & Medicine, vol. 45, no. 5, pp. 726–731, 2008. View at: Publisher Site | Google Scholar
  54. R. A. Maki, V. A. Tyurin, R. C. Lyon et al., “Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease,” The Journal of Biological Chemistry, vol. 284, no. 5, pp. 3158–3169, 2009. View at: Publisher Site | Google Scholar
  55. Y. Matsuo, H. Onodera, Y. Shiga et al., “Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion,” Stroke, vol. 25, no. 7, pp. 1469–1475, 1994. View at: Publisher Site | Google Scholar
  56. D. K. Choi, S. Pennathur, C. Perier et al., “Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson’s disease in mice,” The Journal of Neuroscience, vol. 25, no. 28, pp. 6594–6600, 2005. View at: Publisher Site | Google Scholar
  57. F. Lanza, “Clinical manifestation of myeloperoxidase deficiency,” Journal of Molecular Medicine (Berlin, Germany), vol. 76, no. 10, pp. 676–681, 1998. View at: Publisher Site | Google Scholar
  58. D. I. Pattison and M. J. Davies, “Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds,” Chemical Research in Toxicology, vol. 14, no. 10, pp. 1453–1464, 2001. View at: Publisher Site | Google Scholar
  59. J. Winter, M. Ilbert, P. C. F. Graf, D. Özcelik, and U. Jakob, “Bleach activates a redox-regulated chaperone by oxidative protein unfolding,” Cell, vol. 135, no. 4, pp. 691–701, 2008. View at: Publisher Site | Google Scholar
  60. L. J. Hazell, J. J. M. van den Berg, and R. Stocker, “Oxidation of low-density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation,” The Biochemical Journal, vol. 302, no. 1, pp. 297–304, 1994, Pt 1. View at: Publisher Site | Google Scholar
  61. E. Malle, C. Woenckhaus, G. Waeg, H. Esterbauer, E. F. Gröne, and H. J. Gröne, “Immunological evidence for hypochlorite-modified proteins in human kidney,” The American Journal of Pathology, vol. 150, no. 2, pp. 603–615, 1997. View at: Google Scholar
  62. G. Yu, S. Zheng, and H. Zhang, “Inhibition of myeloperoxidase by N-acetyl lysyltyrosylcysteine amide reduces experimental autoimmune encephalomyelitis-induced injury and promotes oligodendrocyte regeneration and neurogenesis in a murine model of progressive multiple sclerosis,” Neuroreport, vol. 29, no. 3, pp. 208–213, 2018. View at: Publisher Site | Google Scholar
  63. I. Volf, A. Roth, J. Cooper, T. Moeslinger, and E. Koller, “Hypochlorite modified LDL are a stronger agonist for platelets than copper oxidized LDL,” FEBS Letters, vol. 483, no. 2-3, pp. 155–159, 2000. View at: Publisher Site | Google Scholar
  64. G. Marsche, M. Semlitsch, A. Hammer et al., “Hypochlorite-modified albumin colocalizes with RAGE in the artery wall and promotes MCP-1 expression via the RAGE-Erk1/2 MAP-kinase pathway,” The FASEB Journal, vol. 21, no. 4, pp. 1145–1152, 2007. View at: Publisher Site | Google Scholar
  65. D. D. Tang, H. X. Niu, F. F. Peng et al., “Hypochlorite-Modified Albumin Upregulates ICAM-1 Expressionviaa MAPK–NF-κB Signaling Cascade: Protective Effects of Apocynin,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1852340, 14 pages, 2016. View at: Publisher Site | Google Scholar
  66. L. Li Zhou, F. F. Hou, G. B. Wang et al., “Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms,” Kidney International, vol. 76, no. 11, pp. 1148–1160, 2009. View at: Publisher Site | Google Scholar
  67. V. Y. Reddy, P. E. Desorchers, S. V. Pizzo et al., “Oxidative dissociation of human alpha 2-macroglobulin tetramers into dysfunctional dimers,” The Journal of Biological Chemistry, vol. 269, no. 6, pp. 4683–4691, 1994. View at: Google Scholar
  68. T. Siddiqui, M. K. Zia, S. S. Ali, H. Ahsan, and F. H. Khan, “Insight into the interactions of proteinase inhibitor- alpha-2-macroglobulin with hypochlorite,” International Journal of Biological Macromolecules, vol. 117, pp. 401–406, 2018. View at: Publisher Site | Google Scholar
  69. S. M. Wu and S. V. Pizzo, “Alpha(2)-macroglobulin from rheumatoid arthritis synovial fluid: functional analysis defines a role for oxidation in inflammation,” Archives of Biochemistry and Biophysics, vol. 391, no. 1, pp. 119–126, 2001. View at: Publisher Site | Google Scholar
  70. S. M. Wu, C. M. Boyer, and S. V. Pizzo, “The binding of receptor-recognized alpha2-macroglobulin to the low density lipoprotein receptor-related protein and the alpha2M signaling receptor is decoupled by oxidation,” The Journal of Biological Chemistry, vol. 272, no. 33, pp. 20627–20635, 1997. View at: Publisher Site | Google Scholar
  71. S. K. Moestrup and J. Gliemann, “Analysis of ligand recognition by the purified alpha 2-macroglobulin receptor (low density lipoprotein receptor-related protein) Evidence that high affinity of alpha 2-macroglobulin-proteinase complex is achieved by binding to adjacent receptors,” The Journal of Biological Chemistry, vol. 266, no. 21, pp. 14011–14017, 1991. View at: Google Scholar
  72. J. J. Abbink, A. M. Kamp, E. J. Nieuwenhuys, J. H. Nuijens, A. J. G. Swaak, and C. E. Hack, “Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic joints,” Arthritis and Rheumatism, vol. 34, no. 9, pp. 1139–1150, 1991. View at: Publisher Site | Google Scholar
  73. S. M. Wu and S. V. Pizzo, “Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin,” Biochemistry, vol. 38, no. 42, pp. 13983–13990, 1999. View at: Publisher Site | Google Scholar
  74. S. M. Wu, D. D. Patel, and S. V. Pizzo, “Oxidized α2-Macroglobulin (α2M) Differentially Regulates Receptor Binding by Cytokines/Growth Factors: Implications for Tissue Injury and Repair Mechanisms in Inflammation,” Journal of Immunology, vol. 161, no. 8, pp. 4356–4365, 1998. View at: Google Scholar
  75. M. Shingu, S. Nonaka, H. Nishimukai, M. Nobunaga, H. Kitamura, and K. Tomo-Oka, “Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils,” Clinical and Experimental Immunology, vol. 90, no. 1, pp. 72–78, 1992. View at: Publisher Site | Google Scholar
  76. W. Vogt, “Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes,” Immunobiology, vol. 195, no. 3, pp. 334–346, 1996. View at: Publisher Site | Google Scholar
  77. S. J. Weiss, “Tissue destruction by neutrophils,” The New England Journal of Medicine, vol. 320, no. 6, pp. 365–376, 1989. View at: Publisher Site | Google Scholar
  78. K. Devriendt, H. van den Berghe, J. J. Cassiman, and P. Marynen, “Primary structure of pregnancy zone protein. Molecular cloning of a full-length PZP cDNA clone by the polymerase chain reaction,” Biochimica et Biophysica Acta, vol. 1088, no. 1, pp. 95–103, 1991. View at: Publisher Site | Google Scholar
  79. G. A. Chiabrando, M. C. Sánchez, E. L. Skornicka, and P. H. Koo, “Low-density lipoprotein receptor-related protein mediates in PC12 cell cultures the inhibition of nerve growth factor-promoted neurite outgrowth by pregnancy zone protein and alpha2-macroglobulin,” Journal of Neuroscience Research, vol. 70, no. 1, pp. 57–64, 2002. View at: Publisher Site | Google Scholar
  80. A. Philip, L. Bostedt, T. Stigbrand, and M. D. O'connor-McCourt, “Binding of transforming growth factor‐β (TGF‐β) to pregnancy zone protein (PZP),” European Journal of Biochemistry, vol. 221, no. 2, pp. 687–693, 1994. View at: Publisher Site | Google Scholar
  81. E. L. Skornicka, N. Kiyatkina, M. C. Weber, M. L. Tykocinski, and P. H. Koo, “Pregnancy zone protein is a carrier and modulator of placental protein-14 in T-cell growth and cytokine production,” Cellular Immunology, vol. 232, no. 1-2, pp. 144–156, 2004. View at: Publisher Site | Google Scholar
  82. L. Ekelund and C. . B. Laurell, “The pregnancy zone protein response during gestation: a metabolic challenge,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 54, no. 8, pp. 623–629, 1994. View at: Publisher Site | Google Scholar
  83. L. IJsselstijn, L. J. M. Dekker, C. Stingl et al., “Serum levels of pregnancy zone protein are elevated in presymptomatic Alzheimer’s disease,” Journal of Proteome Research, vol. 10, no. 11, pp. 4902–4910, 2011. View at: Publisher Site | Google Scholar
  84. D. A. T. Nijholt, L. Ijsselstijn, M. M. van der Weiden et al., “Pregnancy zone protein is increased in the Alzheimer’s disease brain and associates with senile plaques,” Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 227–238, 2015. View at: Publisher Site | Google Scholar
  85. A. Henderson-Smith, J. J. Corneveaux, M. de Both et al., “Next-generation profiling to identify the molecular etiology of Parkinson dementia,” Neurology Genetics, vol. 2, no. 3, p. e75, 2016. View at: Publisher Site | Google Scholar
  86. C. Horne, A. W. Thomson, C. B. Hunter, A. M. Tunstall, C. M. Towler, and M. E. Billingham, “Pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) and various acute phase reactants in rheumatoid arthritis and osteoarthritis,” Biomedicine, vol. 30, no. 2, pp. 90–94, 1979. View at: Google Scholar
  87. A. W. Thomson, T. Lehner, M. Adinolfi, and C. H. W. Horne, “Pregnancy-associated alpha-2-glycoprotein in recurrent oral ulceration and Behçet’s syndrome,” International Archives of Allergy and Immunology, vol. 66, no. 1, pp. 33–39, 1981. View at: Publisher Site | Google Scholar
  88. L. Beckman, K. Bergdahl, B. Cedergren et al., “Increased serum levels of the pregnancy zone protein in psoriasis,” Acta Dermato-Venereologica, vol. 57, no. 5, pp. 403–406, 1977. View at: Google Scholar
  89. L. Beckman, K. Bergdahl, B. Cedergren et al., “Association between Duffy blood groups and serum level of the pregnancy zone protein,” Human Heredity, vol. 29, no. 5, pp. 257–260, 1979. View at: Publisher Site | Google Scholar
  90. A. Ramos et al., “Trypanosoma cruzi: cruzipain and membrane-bound cysteine proteinase isoform(s) interacts with human alpha(2)-macroglobulin and pregnancy zone protein,” Experimental Parasitology, vol. 100, no. 2, pp. 121–130, 2002. View at: Publisher Site | Google Scholar
  91. E. J. Sarcione and W. C. Biddle, “Elevated serum pregnancy zone protein levels in HIV-1-infected men,” AIDS, vol. 15, no. 18, pp. 2467–2469, 2001. View at: Publisher Site | Google Scholar
  92. J. A. Zarzur, M. Aldao, S. Sileoni, and M. A. Vides, “Serum pregnancy-associated alpha 2-glycoprotein levels in the evolution of hepatitis B virus infection,” Journal of Clinical Laboratory Analysis, vol. 3, no. 2, pp. 73–77, 1989. View at: Publisher Site | Google Scholar
  93. E. Viennois, M. T. Baker, B. Xiao, L. Wang, H. Laroui, and D. Merlin, “Longitudinal study of circulating protein biomarkers in inflammatory bowel disease,” Journal of Proteomics, vol. 112, pp. 166–179, 2015. View at: Publisher Site | Google Scholar
  94. W. H. Stimson, “Variations in the level of a pregnancy-associated alpha-macroglobulin in patients with cancer,” Journal of Clinical Pathology, vol. 28, no. 11, pp. 868–871, 1975. View at: Publisher Site | Google Scholar
  95. F. E. Zalazar, G. A. Chiabrando, N. A. de Aldao, F. Ojeda, M. A. Vides, and M. A. J. Aldao, “Pregnancy-associated α2-glycoprotein in children with acute lymphocytic leukemia, Hodgkin’s disease and non-Hodgkin’s lymphomas,” Clinica Chimica Acta, vol. 210, no. 1-2, pp. 133–138, 1992. View at: Publisher Site | Google Scholar
  96. A. Unger, A. Kay, A. J. Griffin, and G. S. Panayi, “Disease activity and pregnancy associated alpha 2-glycoprotein in rheumatoid arthritis during pregnancy,” British Medical Journal (Clinical Research Ed.), vol. 286, no. 6367, pp. 750–752, 1983. View at: Publisher Site | Google Scholar
  97. J. H. Cater, J. R. Kumita, R. Zeineddine Abdallah et al., “Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer’s-associated amyloid beta peptide,” Proceedings of the National Academy of Sciences, vol. 116, no. 13, pp. 6101–6110, 2019. View at: Publisher Site | Google Scholar
  98. Y. Zhang, X. Wei, S. Browning, G. Scuderi, L. S. Hanna, and L. Wei, “Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection,” Arthritis Research & Therapy, vol. 19, no. 1, pp. 175–175, 2017. View at: Publisher Site | Google Scholar
  99. J. Leipner and R. Saller, “Systemic enzyme therapy in oncology,” Drugs, vol. 59, no. 4, pp. 769–780, 2000. View at: Publisher Site | Google Scholar
  100. G. Lorkowski, “Gastrointestinal absorption and biological activities of serine and cysteine proteases of animal and plant origin: review on absorption of serine and cysteine proteases,” International Journal of Physiology, Pathophysiology and Pharmacology, vol. 4, no. 1, pp. 10–27, 2012. View at: Google Scholar
  101. M. T. Heneka, M. J. Carson, J. E. Khoury et al., “Neuroinflammation in Alzheimer’s disease,” The Lancet Neurology, vol. 14, no. 4, pp. 388–405, 2015. View at: Publisher Site | Google Scholar

Copyright © 2019 Jordan H. Cater et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1182 Views | 303 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19.