CoChat
Sign Up
Cited by 70Alzheimer's disease research and treatmentsRedox biology and oxidative stressDementia and Cognitive Impairment Research

Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3

Open access
Yang, Hongmei, Oh, Chang-ki, Amal, Haitham, Wishnok, John S., Lewis, Sarah, Schahrer, Emily, Trudler, Dorit, Nakamura, Tomohiro +2 more·2022·Science Advances
DOI 10.1126/sciadv.ade0764PMC PMC9750152
Open this paper in CoChat — free account

Abstract

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine ( SNO TRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/sciadv.ade0764

Cites

17 of 17 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 78

  1. [1]A. Caccamo, C. Branca, I. S. Piras, E. Ferreira, M. J. Huentelman, W. S. Liang, B. Readhead, J. T. Dudley, E. E. Spangenberg, K. N. Green, R. Belfiore, W. Winslow, S. Oddo, Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236– 1246 (2017). 28758999
  2. [2]C. Zuccato, E. Cattaneo, Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 5, 311– 322 (2009). 19498435
  3. [3]G. M. McKhann, D. S. Knopman, H. Chertkow, B. T. Hyman, C. R. Jack Jr., C. H. Kawas, W. E. Klunk, W. J. Koroshetz, J. J. Manly, R. Mayeux, R. C. Mohs, J. C. Morris, M. N. Rossor, P. Scheltens, M. C. Carrillo, B. Thies, S. Weintraub, C. H. Phelps, The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 263– 269 (2011). 21514250 PMC3312024
  4. [4]A. Katsnelson, B. De Strooper, H. Y. Zoghbi, Neurodegeneration: From cellular concepts to clinical applications. Sci. Transl. Med. 8, 364ps318 (2016). 27831899
  5. [5]S. V. Jones, I. Kounatidis, Nuclear Factor-Kappa B and Alzheimer disease, unifying genetic and environmental risk factors from cell to humans. Front. Immunol. 8, 1805 (2017). 29312321 PMC5732234
  6. [6]E. C. B. Johnson, E. B. Dammer, D. M. Duong, L. Ping, M. Zhou, L. Yin, L. A. Higginbotham, A. Guajardo, B. White, J. C. Troncoso, M. Thambisetty, T. J. Montine, E. B. Lee, J. Q. Trojanowski, T. G. Beach, E. M. Reiman, V. Haroutunian, M. Wang, E. Schadt, B. Zhang, D. W. Dickson, N. Ertekin-Taner, T. E. Golde, V. A. Petyuk, P. L. De Jager, D. A. Bennett, T. S. Wingo, S. Rangaraju, I. Hajjar, J. M. Shulman, J. J. Lah, A. I. Levey, N. T. Seyfried, Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat. Med. 26, 769– 780 (2020). 32284590 PMC7405761
  7. [7]Z. Deng, K. Purtell, V. Lachance, M. S. Wold, S. Chen, Z. Yue, Autophagy receptors and neurodegenerative diseases. Trends Cell Biol. 27, 491– 504 (2017). 28169082
  8. [8]D. M. Cairns, N. Rouleau, R. N. Parker, K. G. Walsh, L. Gehrke, D. L. Kaplan, A 3D human brain-like tissue model of herpes-induced Alzheimer's disease. Sci. Adv. 6, eaay8828 (2020). 32494701 PMC7202879
  9. [10]D. Gate, N. Saligrama, O. Leventhal, A. C. Yang, M. S. Unger, J. Middeldorp, K. Chen, B. Lehallier, D. Channappa, M. B. De Los Santos, A. M. Bride, J. Pluvinage, F. Elahi, G. K.-Y. Tam, Y. Kim, M. Greicius, A. D. Wagner, L. Aigner, D. R. Galasko, M. M. Davis, T. Wyss-Coray, Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature 577, 399– 404 (2020). 31915375 PMC7445078
  10. [12]T. Arakhamia, C. E. Lee, Y. Carlomagno, D. M. Duong, S. R. Kundinger, K. Wang, D. Williams, M. De Ture, D. W. Dickson, C. N. Cook, N. T. Seyfried, L. Petrucelli, A. W. P. Fitzpatrick, Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell 180, 633– 644.e12 (2020). 32032505 PMC7491959
  11. [13]L. Wang, H. Qi, Y. Tang, H. M. Shen, Post-translational modifications of key machinery in the control of mitophagy. Trends Biochem. Sci. 45, 58– 75 (2020). 31606339
  12. [14]D. Vucic, V. M. Dixit, I. E. Wertz, Ubiquitylation in apoptosis: A post-translational modification at the edge of life and death. Nat. Rev. Mol. Cell Biol. 12, 439– 452 (2011). 21697901
  13. [16]A. P. Wingo, W. Fan, D. M. Duong, E. S. Gerasimov, E. B. Dammer, Y. Liu, N. V. Harerimana, B. White, M. Thambisetty, J. C. Troncoso, N. Kim, J. A. Schneider, I. M. Hajjar, J. J. Lah, D. A. Bennett, N. T. Seyfried, A. I. Levey, T. S. Wingo, Shared proteomic effects of cerebral atherosclerosis and Alzheimer's disease on the human brain. Nat. Neurosci. 23, 696– 700 (2020). 32424284 PMC7269838
  14. [17]B. G. Hill, B. P. Dranka, S. M. Bailey, J. R. Lancaster Jr., V. M. Darley-Usmar, What part of NO don't you understand? Some answers to the cardinal questions in nitric oxide biology. J. Biol. Chem. 285, 19699– 19704 (2010). 20410298 PMC2888379
  15. [18]R. A. Ramachandran, C. Lupfer, H. Zaki, The inflammasome: Regulation of nitric oxide and antimicrobial host defence. Adv. Microb. Physiol. 72, 65– 115 (2018). 29778217
  16. [19]J. Garthwaite, S. L. Charles, R. Chess-Williams, Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385– 388 (1988). 2904125
  17. [20]C. T. Stomberski, D. T. Hess, J. S. Stamler, Protein S-nitrosylation: Determinants of specificity and enzymatic regulation of S-nitrosothiol-based signaling. Antioxid. Redox Signal. 30, 1331– 1351 (2019). 29130312 PMC6391618
  18. [21]B. C. Smith, M. A. Marletta, Mechanisms of S-nitrosothiol formation and selectivity in nitric oxide signaling. Curr. Opin. Chem. Biol. 16, 498– 506 (2012). 23127359 PMC3518608
  19. [22]T. Nakamura, S. A. Lipton, Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases. Trends Pharmacol. Sci. 37, 73– 84 (2016). 26707925 PMC4698225
  20. [23]H. Amal, B. Barak, V. Bhat, G. Gong, B. A. Joughin, X. Wang, J. S. Wishnok, G. Feng, S. R. Tannenbaum, Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function. Mol. Psychiatry 25, 1835– 1848 (2020). 29988084 PMC6614015
  21. [24]M. W. Akhtar, S. Sanz-Blasco, N. Dolatabadi, J. Parker, K. Chon, M. S. Lee, W. Soussou, S. R. McKercher, R. Ambasudhan, T. Nakamura, S. A. Lipton, Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat. Commun. 7, 10242 (2016). 26743041 PMC4729876
  22. [25]H. Amal, G. Gong, E. Gjoneska, S. M. Lewis, J. S. Wishnok, L.-H. Tsai, S. R. Tannenbaum, S-Nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy. Transl. Psychiatry 9, 44 (2019). 30696811 PMC6351542
  23. [26]M. Kartawy, I. Khaliulin, H. Amal, Systems biology reveals reprogramming of the S-nitroso-proteome in the cortical and striatal regions of mice during aging process. Sci. Rep. 10, 13913 (2020). 32807865 PMC7431412
  24. [27]Y. Li, Y. Zhang, L. Wang, P. Wang, Y. Xue, X. Li, X. Qiao, X. Zhang, T. Xu, G. Liu, P. Li, C. Chen, Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. Autophagy 13, 1145– 1160 (2017). 28633005 PMC5529069
  25. [28]M. Kashiba-Iwatsuki, K. Kitoh, E. Kasahara, H. Yu, M. Nisikawa, M. Matsuo, M. Inoue, Ascorbic acid and reducing agents regulate the fates and functions of S-nitrosothiols. J. Biochem. 122, 1208– 1214 (1997). 9498567
  26. [29]A. P. Dicks, D. L. Williams, Generation of nitric oxide from S-nitrosothiols using protein-bound Cu2+ sources. Chem. Biol. 3, 655– 659 (1996). 8807899
  27. [30]L. M. Lopez-Sanchez, C. Lopez-Pedrera, A. Rodriguez-Ariza, Proteomic approaches to evaluate protein S-nitrosylation in disease. Mass Spectrom. Rev. 33, 7– 20 (2014). 23775552
  28. [32]N. Zhan, C. Wang, L. Chen, H. Yang, J. Feng, X. Gong, B. Ren, R. Wu, J. Mu, Y. Li, Z. Liu, Y. Zhou, J. Peng, K. Wang, X. Huang, S. Xiao, J. Zuo, S-Nitrosylation targets GSNO reductase for selective autophagy during hypoxia responses in plants. Mol. Cell 71, 142– 154.e6 (2018). 30008318
  29. [33]T. Nakamura, L. Wang, C. C. L. Wong, F. L. Scott, B. P. Eckelman, X. Han, C. Tzitzilonis, F. Meng, Z. Gu, E. A. Holland, A. T. Clemente, S.-I. Okamoto, G. S. Salvesen, R. Riek, J. R. Yates III, S. A. Lipton, Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Mol. Cell 39, 184– 195 (2010). 20670888 PMC2924818
  30. [34]L. M. Landino, M. T. Koumas, C. E. Mason, J. A. Alston, Ascorbic acid reduction of microtubule protein disulfides and its relevance to protein S-Nitrosylation assays. Biochem. Biophys. Res. Commun. 340, 347– 352 (2006). 16375859
  31. [35]P.-T. Doulias, M. Tenopoulou, K. Raju, L. A. Spruce, S. H. Seeholzer, H. Ischiropoulos, Site specific identification of endogenous S-nitrosocysteine proteomes. J. Proteomics 92, 195– 203 (2013). 23748021 PMC3818367
  32. [36]R. Mnatsakanyan, S. Markoutsa, K. Walbrunn, A. Roos, S. H. L. Verhelst, R. P. Zahedi, Proteome-wide detection of S-nitrosylation targets and motifs using bioorthogonal cleavable-linker-based enrichment and switch technique. Nat. Commun. 10, 2195 (2019). 31097712 PMC6522481
  33. [37]M. T. Forrester, J. W. Thompson, M. W. Foster, L. Nogueira, M. A. Moseley, J. S. Stamler, Proteomic analysis of S-nitrosylation and denitrosylation by resin-assisted capture. Nat. Biotechnol. 27, 557– 559 (2009). 19483679 PMC2891235
  34. [38]U. Seneviratne, L. C. Godoy, J. S. Wishnok, G. N. Wogan, S. R. Tannenbaum, Mechanism-based triarylphosphine-ester probes for capture of endogenous RSNOs. J. Am. Chem. Soc. 135, 7693– 7704 (2013). 23614769 PMC3663071
  35. [39]U. Seneviratne, A. Nott, V. B. Bhat, K. C. Ravindra, J. S. Wishnok, L.-H. Tsai, S. R. Tannenbaum, S-Nitrosation of proteins relevant to Alzheimer's disease during early stages of neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 113, 4152– 4157 (2016). 27035958 PMC4839463
  36. [41]I. Khaliulin, M. Kartawy, H. Amal, Sex differences in biological processes and nitrergic signaling in mouse brain. Biomedicine 8, 124 (2020). PMC7277573 32429146
  37. [42]P. Fernández-Vizarra, A. P. Fernández, S. Castro-Blanco, J. M. Encinas, J. Serrano, M. L. Bentura, P. Muñoz, R. Martínez-Murillo, J. Rodrigo, Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Neurobiol. Dis. 15, 287– 305 (2004). 15006699
  38. [43]R. A. Nebel, N. T. Aggarwal, L. L. Barnes, A. Gallagher, J. M. Goldstein, K. Kantarci, M. P. Mallampalli, E. C. Mormino, L. Scott, W. H. Yu, P. M. Maki, M. M. Mielke, Understanding the impact of sex and gender in Alzheimer's disease: A call to action. Alzheimers Dement. 14, 1171– 1183 (2018). 29907423 PMC6400070
  39. [44]H. Mathys, J. Davila-Velderrain, Z. Peng, F. Gao, S. Mohammadi, J. Z. Young, M. Menon, L. He, F. Abdurrob, X. Jiang, A. J. Martorell, R. M. Ransohoff, B. P. Hafler, D. A. Bennett, M. Kellis, L.-H. Tsai, Single-cell transcriptomic analysis of Alzheimer's disease. Nature 570, 332– 337 (2019). 31042697 PMC6865822
  40. [46]J. L. Podcasy, C. N. Epperson, Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin. Neurosci. 18, 437– 446 (2016). 28179815 PMC5286729
  41. [47]M. Asai, A. Kinjo, S. Kimura, R. Mori, T. Kawakubo, K. Shirotani, S. Yagishita, K. Maruyama, N. Iwata, Perturbed calcineurin-NFAT signaling is associated with the development of Alzheimer's disease. Biol. Pharm. Bull. 39, 1646– 1652 (2016). 27725441
  42. [48]W. D. Parker Jr., J. Parks, C. M. Filley, B. K. Kleinschmidt-DeMasters, Electron transport chain defects in Alzheimer's disease brain. Neurology 44, 1090– 1096 (1994). 8208407
  43. [49]D. M. Bonifati, U. Kishore, Role of complement in neurodegeneration and neuroinflammation. Mol. Immunol. 44, 999– 1010 (2007). 16698083
  44. [50]B. Stevens, N. J. Allen, L. E. Vazquez, G. R. Howell, K. S. Christopherson, N. Nouri, K. D. Micheva, A. K. Mehalow, A. D. Huberman, B. Stafford, A. Sher, A. M. Litke, J. D. Lambris, S. J. Smith, S. W. M. John, B. A. Barres, The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164– 1178 (2007). 18083105
  45. [51]J. C. Tam, S. R. Bidgood, W. A. McEwan, L. C. James, Intracellular sensing of complement C3 activates cell autonomous immunity. Science 345, 1256070 (2014). 25190799 PMC4172439
  46. [52]M. Maier, Y. Peng, L. Jiang, T. J. Seabrook, M. C. Carroll, C. A. Lemere, Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J. Neurosci. 28, 6333– 6341 (2008). 18562603 PMC3329761
  47. [53]S. M. Carpanini, M. Torvell, B. P. Morgan, Therapeutic inhibition of the complement system in diseases of the central nervous system. Front. Immunol. 10, 362 (2019). 30886620 PMC6409326
  48. [55]D. Trudler, K. L. Nazor, Y. S. Eisele, T. Grabauskas, N. Dolatabadi, J. Parker, A. Sultan, Z. Zhong, M. S. Goodwin, Y. Levites, T. E. Golde, J. W. Kelly, M. R. Sierks, N. J. Schork, M. Karin, R. Ambasudhan, S. A. Lipton, Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc. Natl. Acad. Sci. U.S.A. 118, e2025847118 (2021). 33833060 PMC8054017
  49. [56]E. Vegeto, C. Bonincontro, G. Pollio, A. Sala, S. Viappiani, F. Nardi, A. Brusadelli, B. Viviani, P. Ciana, A. Maggi, Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J. Neurosci. 21, 1809– 1818 (2001). 11245665 PMC6762610
  50. [57]S. Lively, L. C. Schlichter, Microglia responses to pro-inflammatory stimuli (LPS, IFNγ+TNFα) and reprogramming by resolving cytokines (IL-4, IL-10). Front. Cell. Neurosci. 12, 215 (2018). 30087595 PMC6066613
  51. [58]R. D. Terry, E. Masliah, D. P. Salmon, N. Butters, R. De Teresa, R. Hill, L. A. Hansen, R. Katzman, Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572– 580 (1991). 1789684
  52. [60]S. Ghatak, N. Dolatabadi, R. Gao, Y. Wu, H. Scott, D. Trudler, A. Sultan, R. Ambasudhan, T. Nakamura, E. Masliah, M. Talantova, B. Voytek, S. A. Lipton, NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models. Mol. Psychiatry 26, 5751– 5765 (2021). 32467645 PMC7704704
  53. [61]T. S. Wijasa, M. Sylvester, N. Brocke-Ahmadinejad, S. Schwartz, F. Santarelli, V. Gieselmann, T. Klockgether, F. Brosseron, M. T. Heneka, Quantitative proteomics of synaptosome S-nitrosylation in Alzheimer's disease. J. Neurochem. 152, 710– 726 (2020). 31520481
  54. [62]D. K. Bhatt, B. Prasad, Critical issues and optimized practices in quantification of protein abundance level to determine interindividual variability in DMET proteins by LC-MS/MS proteomics. Clin. Pharmacol. Ther. 103, 619– 630 (2018). 28833066 PMC5816727
  55. [63]W. Bittremieux, D. L. Tabb, F. Impens, A. Staes, E. Timmerman, L. Martens, K. Laukens, Quality control in mass spectrometry-based proteomics. Mass Spectrom. Rev. 37, 697– 711 (2018). 28802010
  56. [64]U. Kaur, P. Banerjee, A. Bir, M. Sinha, A. Biswas, S. Chakrabarti, Reactive oxygen species, redox signaling and neuroinflammation in Alzheimer's disease: The NF-κB connection. Curr. Top. Med. Chem. 15, 446– 457 (2015). 25620241
  57. [65]G. Poste, Bring on the biomarkers. Nature 469, 156– 157 (2011). 21228852
  58. [69]S. Ma, I. Y. Attarwala, X. Q. Xie, SQSTM1/p62: A potential target for neurodegenerative disease. ACS Chem. Nerosci. 10, 2094– 2114 (2019). PMC6712989 30657305
  59. [70]T. B. Haack, E. Ignatius, J. Calvo-Garrido, A. Iuso, P. Isohanni, C. Maffezzini, T. Lönnqvist, A. Suomalainen, M. Gorza, L. S. Kremer, E. Graf, M. Hartig, R. Berutti, M. Paucar, P. Svenningsson, H. Stranneheim, G. Brandberg, A. Wedell, M. A. Kurian, S. A. Hayflick, P. Venco, V. Tiranti, T. M. Strom, M. Dichgans, R. Horvath, E. Holinski-Feder, C. Freyer, T. Meitinger, H. Prokisch, J. Senderek, A. Wredenberg, C. J. Carroll, T. Klopstock, Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. Am. J. Hum. Genet. 99, 735– 743 (2016). 27545679 PMC5010644
  60. [73]A. Salminen, K. Kaarniranta, A. Haapasalo, M. Hiltunen, H. Soininen, I. Alafuzoff, Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease. Prog. Neurobiol. 96, 87– 95 (2012). 22138392
  61. [74]A. Caccamo, E. Ferreira, C. Branca, S. Oddo, p62 improves AD-like pathology by increasing autophagy. Mol. Psychiatry 22, 865– 873 (2017). 27573878 PMC5479312
  62. [75]H. Cha-Molstad, J. E. Yu, Z. Feng, S. H. Lee, J. G. Kim, P. Yang, B. Han, K. W. Sung, Y. D. Yoo, J. Hwang, T. M. Guire, S. M. Shim, H. D. Song, S. Ganipisetti, N. Wang, J. M. Jang, M. J. Lee, S. J. Kim, K. H. Lee, J. T. Hong, A. Ciechanover, I. Mook-Jung, K. P. Kim, X.-Q. Xie, Y. T. Kwon, B. Y. Kim, p62/SQSTM1/sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat. Commun. 8, 102 (2017). 28740232 PMC5524641
  63. [76]Y. Du, M. C. Wooten, M. W. Wooten, Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol. Dis. 35, 302– 310 (2009). 19481605 PMC2718328
  64. [77]Y. Du, M. C. Wooten, M. Gearing, M. W. Wooten, Age-associated oxidative damage to the p62 promoter: Implications for Alzheimer disease. Free Radic. Biol. Med. 46, 492– 501 (2009). 19071211 PMC2684672
  65. [78]R. V. Farese, M. P. Sajan, in Genetics, Neurology, Behavior, and Diet in Dementia, C. R. Martin, V. R. Preedy, Eds. (Academic Press, 2020), vol. 2 chap. 13, pp. 195–212.
  66. [79]C.-K. Oh, N. Dolatabadi, P. Cieplak, M. T. Diaz-Meco, J. Moscat, J. P. Nolan, T. Nakamura, S. A. Lipton, S-Nitrosylation of p62 inhibits autophagic flux to promote α-synuclein secretion and spread in Parkinson's disease and Lewy body dementia. J. Neurosci. 42, 3011– 3024 (2022). 35169022 PMC8985870
  67. [80]J.-I. Satoh, Y. Kino, Y. Yamamoto, N. Kawana, T. Ishida, Y. Saito, K. Arima, PLD3 is accumulated on neuritic plaques in Alzheimer's disease brains. Alzheimers Res. Ther. 6, 70 (2014). 25478031 PMC4255636
  68. [81]A. S. Mukadam, S. Y. Breusegem, M. N. J. Seaman, Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing. Cell. Mol. Life Sci. 75, 2613– 2625 (2018). 29368044 PMC6003983
  69. [82]A. L. Gavin, D. Huang, C. Huber, A. Mårtensson, V. Tardif, P. D. Skog, T. R. Blane, T. C. Thinnes, K. Osborn, H. S. Chong, F. Kargaran, P. Kimm, A. Zeitjian, R. L. Sielski, M. Briggs, S. R. Schulz, A. Zarpellon, B. Cravatt, E. S. Pang, J. Teijaro, J. C. de la Torre, M. O’Keeffe, H. Hochrein, M. Damme, L. Teyton, B. R. Lawson, D. Nemazee, PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat. Immunol. 19, 942– 953 (2018). 30111894 PMC6105523
  70. [83]M. S. Tan, J. X. Zhu, X. P. Cao, J. T. Yu, L. Tan, Rare variants in PLD3 increase risk for Alzheimer's disease in Han Chinese. J. Alzheimers Dis. 64, 55– 59 (2018). 29865074
  71. [84]J.-C. Lambert, B. Grenier-Boley, C. Bellenguez, F. Pasquier, D. Campion, J.-F. Dartigues, C. Berr, C. Tzourio, P. Amouyel, PLD3 and sporadic Alzheimer's disease risk. Nature 520, E1 (2015). 25832408
  72. [85]P. Fazzari, K. Horre, A. M. Arranz, C. S. Frigerio, T. Saito, T. C. Saido, B. De Strooper, PLD3 gene and processing of APP. Nature 541, E1– E2 (2017). 28128235
  73. [87]V. L. Nimgaonkar, K. M. Prasad, K. V. Chowdari, E. G. Severance, R. H. Yolken, The complement system: A gateway to gene-environment interactions in schizophrenia pathogenesis. Mol. Psychiatry 22, 1554– 1561 (2017). 28761078 PMC5656502
  74. [89]S. T. DeKosky, S. W. Scheff, Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457– 464 (1990). 2360787
  75. [90]A. Rahman, H. Jackson, H. Hristov, R. S. Isaacson, N. Saif, T. Shetty, O. Etingin, C. Henchcliffe, R. D. Brinton, L. Mosconi, Sex and gender driven modifiers of Alzheimer's: The role for estrogenic control across age, race, medical, and lifestyle risks. Front. Aging Neurosci. 11, 315 (2019). 31803046 PMC6872493
  76. [93]M. Talantova, S. Sanz-Blasco, X. Zhang, P. Xia, M. W. Akhtar, S.-I. Okamoto, G. Dziewczapolski, T. Nakamura, G. Cao, A. E. Pratt, Y.-J. Kang, S. Tu, E. Molokanova, S. R. McKercher, S. A. Hires, H. Sason, D. G. Stouffer, M. W. Buczynski, J. P. Solomon, S. Michael, E. T. Powers, J. W. Kelly, A. Roberts, G. Tong, T. Fang-Newmeyer, J. Parker, E. A. Holland, D. Zhang, N. Nakanishi, H.-S. V. Chen, H. Wolosker, Y. Wang, L. H. Parsons, R. Ambasudhan, E. Masliah, S. F. Heinemann, J. C. Piña-Crespo, S. A. Lipton, Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc. Natl. Acad. Sci. U.S.A. 110, E2518– E2527 (2013). 23776240 PMC3704025
  77. [94]C. M. Sellgren, S. D. Sheridan, J. Gracias, D. Xuan, T. Fu, R. H. Perlis, Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors. Mol. Psychiatry 22, 170– 177 (2017). 27956744 PMC5285468
  78. [95]M. P. van Ooijen, V. L. Jong, M. J. C. Eijkemans, A. J. R. Heck, A. C. Andeweg, N. A. Binai, H.-J. van den Ham, Identification of differentially expressed peptides in high-throughput proteomics data. Brief. Bioinform. 19, 971– 981 (2018). 28369175

Cited by

Sorted by citations

Authors
Yang, H., Oh, C.-K., Amal, H., Wishnok, J. S., Lewis, S., Schahrer, E., Trudler, D., Nakamura, T., Tannenbaum, S. R., & Lipton, S. A.
Affiliations
  • Changchun University of Chinese Medicine (CN)
  • Scripps Research Institute (US)
  • Hebrew University of Jerusalem (IL)
  • Massachusetts Institute of Technology (US)
Corresponding author
  • Yang, Hongmei
  • Oh, Chang-ki
  • Tannenbaum, Steven R.
  • Lipton, Stuart A.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-12-16
Volume
8
Issue
50
Pages
eade0764-eade0764
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.ade0764
PMC
PMC9750152
OpenAlex
W4311441725
Cited by
70
References
17
Citations by year
2026: 13 · 2025: 18 · 2024: 19 · 2023: 19 · 2012: 1
FWCI
9.81
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Supernus Pharmaceuticals
  • Adamas Pharmaceuticals
  • National Institutes of Health
  • National Institute on Aging (RF1AG057409, R01AG061845, R56AG065372, R01AG056259, R01AG078756, R35AG071734)
  • National Institute on Drug Abuse (R01DA048882, DP1DA041722)
  • National Institute of Neurological Disorders and Stroke (R61NS122098, RF1NS123298)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, S-nitrosylation, sex differences, complement C3, beta-estradiol, synaptic loss, cognitive decline, p62, PLD3, post-translational modification
MeSH terms
Alzheimer Disease, Brain, Female, Humans, Male, Protein Processing, Post-Translational, Proteins, Synapses

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review