Neddylation dysfunction in Alzheimer's disease

Journal of Cellular and Molecular Medicine

Volumn 16, Issue 11, 2012, Pages 2583-2591

  Chen, Yuzhi ^a   Neve, Rachael L ^b   Liu, Helena ^c  

^a UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c Massachusetts Institute of Technology Cambridge   (United States)

Author keywords

Alzheimer's disease; APP; Differentiation; NAE1; Neddylation; Neurodegeneration; Neurogenesis; Parkinson's disease; Proteasome; Ubiquitination

Indexed keywords

AMYLOID PRECURSOR PROTEIN; AMYLOID PROTEIN PRECURSOR BINDING PROTEIN 1, HUMAN; AMYLOID PROTEIN PRECURSOR-BINDING PROTEIN 1, HUMAN; CAND1 PROTEIN, HUMAN; CULLIN; CULLIN 1; DNA BINDING PROTEIN; NEDD8 PROTEIN, HUMAN; PROTEASOME; TRANSCRIPTION FACTOR; UBIQUITIN; UBIQUITIN PROTEIN LIGASE;

ALZHEIMER DISEASE; ANIMAL; ARTICLE; GENETICS; HUMAN; METABOLISM; PATHOPHYSIOLOGY; UBIQUITINATION;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; CULLIN PROTEINS; DNA-BINDING PROTEINS; HUMANS; PROTEASOME ENDOPEPTIDASE COMPLEX; TRANSCRIPTION FACTORS; UBIQUITIN-ACTIVATING ENZYMES; UBIQUITINATION; UBIQUITINS;

EID: 84868149287     PISSN: 15821838     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1582-4934.2012.01604.x     Document Type: Article

References (120)

1. Soucy TA, Dick LR, Smith PG, et al. The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy. Genes Cancer. 2010; 1: 708-16.
2. Lincoln C, Britton JH, Estelle M. Growth and development of the axr1 mutants of Arabidopsis. Plant Cell. 1990; 2: 1071-80.
3. Leyser HM, Lincoln CA, Timpte C, et al. Arabidopsis auxin-resistance gene AXR1 encodes a protein related to ubiquitin-activating enzyme E1. Nature. 1993; 364: 161-4.
4. Kumar S, Yoshida Y, Noda M. Cloning of a cDNA which encodes a novel ubiquitin-like protein. Biochem Biophys Res Commun. 1993; 195: 393-9.
5. Liakopoulos D, Doenges G, Matuschewski K, et al. A novel protein modification pathway related to the ubiquitin system. EMBO J. 1998; 17: 2208-14.
6. Osaka F, Kawasaki H, Aida N, et al. A new NEDD8-ligating system for cullin-4A. Genes Dev. 1998; 12: 2263-8.
7. Gong L, Yeh ET. Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J Biol Chem. 1999; 274: 12036-42.
8. Ohta T, Michel JJ, Schottelius AJ, et al. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell. 1999; 3: 535-41.
9. Megumi Y, Miyauchi Y, Sakurai H, et al. Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex. Genes Cells. 2005; 10: 679-91.
10. Swaroop M, Wang Y, Miller P, et al. Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation. Oncogene. 2000; 19: 2855-66.
11. Rabut G, Le Dez G, Verma R, et al. The TFIIH Subunit Tfb3 Regulates Cullin Neddylation. Mol Cell. 2011; 43: 488-95.
12. Benjamin S, Steller H. Another tier for caspase regulation: IAPs as NEDD8 E3 ligases. Dev Cell. 2010; 19: 791-2.
13. Broemer M, Tenev T, Rigbolt KT, et al. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol Cell. 2010; 40: 810-22.
14. Kurz T, Ozlu N, Rudolf F, et al. The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae. Nature. 2005; 435: 1257-61.
15. Kurz T, Chou YC, Willems AR, et al. Dcn1 functions as a scaffold-type e3 ligase for cullin neddylation. Mol Cell. 2008; 29: 23-35.
16. Hirschberg J, Marcus M. Isolation by a replica-plating technique of Chinese hamster temperature-sensitive cell cycle mutants. J Cell Physiol. 1982; 113: 159-66.
17. Handeli S, Weintraub H. The ts41 mutation in Chinese hamster cells leads to successive S phases in the absence of intervening G2, M, and G1. Cell. 1992; 71: 599-611.
18. Cernac A, Lincoln C, Lammer D, et al. The SAR1 gene of Arabidopsis acts downstream of the AXR1 gene in auxin response. Development. 1997; 124: 1583-91.
19. Chen Y, McPhie DL, Hirschberg J, et al. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem. 2000; 275: 8929-35.
20. Soucy TA, Smith PG, Milhollen MA, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458: 732-6.
21. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998; 67: 425-79.
22. Villeneuve NF, Lau A, Zhang DD. Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal. 2010; 13: 1699-712.
23. Harreman M, Taschner M, Sigurdsson S, et al. Distinct ubiquitin ligases act sequentially for RNA polymerase II polyubiquitylation. Proc Natl Acad Sci USA. 2009; 106: 20705-10.
24. van Nocker S, Vierstra RD. Multiubiquitin chains linked through lysine 48 are abundant in vivo and are competent intermediates in the ubiquitin proteolytic pathway. J Biol Chem. 1993; 268: 24766-73.
25. Shang F, Deng G, Liu Q, et al. Lys6-modified ubiquitin inhibits ubiquitin-dependent protein degradation. J Biol Chem. 2005; 280: 20365-74.
26. Acconcia F, Sigismund S, Polo S. Ubiquitin in trafficking: the network at work. Exp Cell Res. 2009; 315: 1610-8.
27. Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001; 2: 195-201.
28. Sun L, Chen ZJ. The novel functions of ubiquitination in signaling. Curr Opin Cell Biol. 2004; 16: 119-26.
29. Duncan LM, Piper S, Dodd RB, et al. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. EMBO J. 2006; 25: 1635-45.
30. Olzmann JA, Chin LS. Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway. Autophagy. 2008; 4: 85-7.
31. Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 2009; 78: 363-97.
32. Moon J, Parry G, Estelle M. The ubiquitin-proteasome pathway and plant development. Plant Cell. 2004; 16: 3181-95.
33. Petroski MD, Deshaies RJ. Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005; 6: 9-20.
34. Bosu DR, Kipreos ET. Cullin-RING ubiquitin ligases: global regulation and activation cycles. Cell Div. 2008; 3: 7.
35. Bennett EJ, Rush J, Gygi SP, et al. Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell. 2010; 143: 951-65.
36. Emanuele MJ, Elia AE, Xu Q, et al. Global Identification of Modular Cullin-RING Ligase Substrates. Cell. 2011; 147: 459-74.
37. Gan-Erdene T, Nagamalleswari K, Yin L, et al. Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem. 2003; 278: 28892-900.
38. Osaka F, Saeki M, Katayama S, et al. Covalent modifier NEDD8 is essential for SCF ubiquitin-ligase in fission yeast. EMBO J. 2000; 19: 3475-84.
39. Duda DM, Borg LA, Scott DC, et al. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell. 2008; 134: 995-1006.
40. Saha A, Deshaies RJ. Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation. Mol Cell. 2008; 32: 21-31.
41. Furukawa M, Zhang Y, McCarville J, et al. The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1. Mol Cell Biol. 2000; 20: 8185-97.
42. Kawakami T, Chiba T, Suzuki T, et al. NEDD8 recruits E2-ubiquitin to SCF E3 ligase. EMBO J. 2001; 20: 4003-12.
43. Read MA, Brownell JE, Gladysheva TB, et al. Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. Mol Cell Biol. 2000; 20: 2326-33.
44. Sufan RI, Ohh M. Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex. Neoplasia. 2006; 8: 956-63.
45. Chew EH, Hagen T. Substrate-mediated regulation of cullin neddylation. J Biol Chem. 2007; 282: 17032-40.
46. Zheng N, Schulman BA, Song L, et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002; 416: 703-9.
47. Gagne JM, Downes BP, Shiu SH, et al. The F-box subunit of the SCF E3 complex is encoded by a diverse superfamily of genes in Arabidopsis. Proc Natl Acad Sci USA. 2002; 99: 11519-24.
48. Jin J, Cardozo T, Lovering RC, et al. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 2004; 18: 2573-80.
49. Chen Y, Liu W, McPhie DL, et al. APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain. J Cell Biol. 2003; 163: 27-33.
50. Xia X, Qian S, Soriano S, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci USA. 2001; 98: 10863-8.
51. Chen Y, Bodles AM. Amyloid precursor protein modulates beta-catenin degradation. J Neuroinflammation. 2007; 4: 29.
52. Wang F, Deng XW. Plant ubiquitin-proteasome pathway and its role in gibberellin signaling. Cell Res. 2011; 21: 1286-94.
53. Cope GA, Deshaies RJ. COP9 signalosome: a multifunctional regulator of SCF and other cullin-based ubiquitin ligases. Cell. 2003; 114: 663-71.
54. Wolf DA, Zhou C, Wee S. The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases? Nat Cell Biol. 2003; 5: 1029-33.
55. Wei N, Serino G, Deng XW. The COP9 signalosome: more than a protease. Trends Biochem Sci. 2008; 33: 592-600.
56. Schwechheimer C. The COP9 signalosome (CSN): an evolutionary conserved proteolysis regulator in eukaryotic development. Biochim Biophys Acta. 2004; 1695: 45-54.
57. Kato JY, Yoneda-Kato N. Mammalian COP9 signalosome. Genes Cells. 2009; 14: 1209-25.
58. Lyapina S, Cope G, Shevchenko A, et al. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science. 2001; 292: 1382-5.
59. Cope GA, Suh GS, Aravind L, et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science. 2002; 298: 608-11.
60. Serino G, Deng XW. The COP9 signalosome: regulating plant development through the control of proteolysis. Annu Rev Plant Biol. 2003; 54: 165-82.
61. Wee S, Geyer RK, Toda T, et al. CSN facilitates Cullin-RING ubiquitin ligase function by counteracting autocatalytic adapter instability. Nat Cell Biol. 2005; 7: 387-91.
62. Wu JT, Lin HC, Hu YC, et al. Neddylation and deneddylation regulate Cul1 and Cul3 protein accumulation. Nat Cell Biol. 2005; 7: 1014-20.
63. Zheng J, Yang X, Harrell JM, et al. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell. 2002; 10: 1519-26.
64. Liu J, Furukawa M, Matsumoto T, et al. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. Mol Cell. 2002; 10: 1511-8.
65. Oshikawa K, Matsumoto M, Yada M, et al. Preferential interaction of TIP120A with Cul1 that is not modified by NEDD8 and not associated with Skp1. Biochem Biophys Res Commun. 2003; 303: 1209-16.
66. Zhang W, Ito H, Quint M, et al. Genetic analysis of CAND1-CUL1 interactions in Arabidopsis supports a role for CAND1-mediated cycling of the SCFTIR1 complex. Proc Natl Acad Sci USA. 2008; 105: 8470-5.
67. Bosu DR, Feng H, Min K, et al. C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues. Dev Biol. 2010; 346: 113-26.
68. Chen Y, Liu W, Naumovski L, et al. ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis. J Neurochem. 2003; 85: 801-9.
69. Iwabuchi K, Bartel PL, Li B, et al. Two cellular proteins that bind to wild-type but not mutant p53. Proc Natl Acad Sci USA. 1994; 91: 6098-102.
70. Naumovski L, Cleary ML. The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M. Mol Cell Biol. 1996; 16: 3884-92.
71. Kampa KM, Bonin M, Lopez CD. New insights into the expanding complexity of the tumor suppressor ASPP2. Cell Cycle. 2009; 8: 2871-6.
72. Oved S, Mosesson Y, Zwang Y, et al. Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases. J Biol Chem. 2006; 281: 21640-51.
73. Lee MR, Lee D, Shin SK, et al. Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8. Biochem Biophys Res Commun. 2008; 366: 976-81.
74. Zheng H, Koo EH. Biology and pathophysiology of the amyloid precursor protein. Mol Neurodegener. 2011; 6: 27.
75. Zhang H, Ma Q, Zhang YW, et al. Proteolytic processing of Alzheimer's beta-amyloid precursor protein. J Neurochem. 2011; 1: 9-21.
76. Chen Y, Bodles AM, McPhie DL, et al. APP-BP1 inhibits Abeta42 levels by interacting with Presenilin-1. Mol Neurodegener. 2007; 2: 3.
77. Chow N, Korenberg JR, Chen XN, et al. APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein. J Biol Chem. 1996; 271: 11339-46.
78. King GD, Scott Turner R. Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk? Exp Neurol. 2004; 185: 208-19.
79. Kerr ML, Small DH. Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development. J Neurosci Res. 2005; 80: 151-9.
80. Laifenfeld D, Patzek LJ, McPhie DL, et al. Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci. 2007; 27: 7141-53.
81. Perez RG, Soriano S, Hayes JD, et al. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. J Biol Chem. 1999; 274: 18851-6.
82. Barbagallo AP, Wang Z, Zheng H, et al. A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J Biol Chem. 2011; 286: 8717-21.
83. Kim AY, Bommelje CC, Lee BE, et al. SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation. J Biol Chem. 2008; 283: 33211-20.
84. Villa C, Venturelli E, Fenoglio C, et al. DCUN1D1 is a risk factor for frontotemporal lobar degeneration. Eur J Neurol. 2009; 16: 870-3.
85. Dil Kuazi A, Kito K, Abe Y, et al. NEDD8 protein is involved in ubiquitinated inclusion bodies. J Pathol. 2003; 199: 259-66.
86. Mori F, Nishie M, Piao YS, et al. Accumulation of NEDD8 in neuronal and glial inclusions of neurodegenerative disorders. Neuropathol Appl Neurobiol. 2005; 31: 53-61.
87. Cripps D, Thomas SN, Jeng Y, et al. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem. 2006; 281: 10825-38.
88. Leidecker O, Matic I, Mahata B, et al. The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions. Cell Cycle. 2012; 11: 1142-50.
89. Hjerpe R, Thomas Y, Kurz T. NEDD8 overexpression should not be used to identify substrates of the NEDD8 pathway. J Mol Biol. 2012; 421: 27-9.
90. Wolfe MS. The gamma-Secretase Complex: Membrane-Embedded Proteolytic Ensemble. Biochemistry. 2006; 45: 7931-9.
91. Ehehalt R, Keller P, Haass C, et al. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003; 160: 113-23.
92. Vetrivel KS, Cheng H, Lin W, et al. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem. 2004; 279: 44945-54.
93. Wu G, Hubbard EJ, Kitajewski JK, et al. Evidence for functional and physical association between Caenorhabditis elegans SEL-10, a Cdc4p-related protein, and SEL-12 presenilin. Proc Natl Acad Sci USA. 1998; 95: 15787-91.
94. Li J, Pauley AM, Myers RL, et al. SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. J Neurochem. 2002; 82: 1540-8.
95. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392: 605-8.
96. Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000; 25: 302-5.
97. Staropoli JF, McDermott C, Martinat C, et al. Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron. 2003; 37: 735-49.
98. Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem. 2000; 275: 35661-4.
99. Olzmann JA, Li L, Chudaev MV, et al. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007; 178: 1025-38.
100. Rodriguez-Navarro JA, Gomez A, Rodal I, et al. Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice. Hum Mol Genet. 2008; 17: 3128-43.
101. Burns MP, Zhang L, Rebeck GW, et al. Parkin promotes intracellular Abeta1-42 clearance. Hum Mol Genet. 2009; 18: 3206-16.
102. Rosen KM, Moussa CE, Lee HK, et al. Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function. J Neurosci Res. 2010; 88: 167-78.
103. Khandelwal PJ, Herman AM, Hoe HS, et al. Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet. 2011; 20: 2091-102.
104. Joo Y, Ha S, Hong BH, et al. Amyloid precursor protein binding protein-1 modulates cell cycle progression in fetal neural stem cells. PLoS ONE. 2010; 5: e14203.
105. Kim HJ, Kim SH, Shim SO, et al. Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development. Cell Death Differ. 2007; 14: 103-15.
106. Tateishi K, Omata M, Tanaka K, et al. The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice. J Cell Biol. 2001; 155: 571-9.
107. Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012; 16: 15-31.
108. Kuwabara T, Hsieh J, Nakashima K, et al. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell. 2004; 116: 779-93.
109. Ma QH, Futagawa T, Yang WL, et al. A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol. 2008; 10: 283-94.
110. Kim WY, Shen J. Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener. 2008; 3: 2.
111. Gadadhar A, Marr R, Lazarov O. Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. J Neurosci. 2011; 31: 2615-23.
112. Hong BH, Ha S, Joo Y, et al. Amyloid precursor protein binding protein-1 knockdown reduces neuronal differentiation in fetal neural stem cells. NeuroReport. 2012; 23: 61-6.
113. Joo Y, Lee SH, Ha S, et al. Focal transient ischemia increases APP-BP1 expression in neural progenitor cells. NeuroReport. 2011; 22: 200-5.
114. Zheng H, Jiang M, Trumbauer ME, et al. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995; 81: 525-31.
115. Tremml P, Lipp HP, Muller U, et al. Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified beta-amyloid precursor protein gene. Behav Brain Res. 1998; 95: 65-76.
116. Chasseigneaux S, Allinquant B. Functions of Abeta, sAPPalpha and sAPPbeta: similarities and differences. J Neurochem. 2012; 120 Suppl 1: 99-108.
117. Chen Y, Dong C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 2009; 16: 386-94.
118. Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci USA. 2004; 101: 343-7.
119. Ziabreva I, Perry E, Perry R, et al. Altered neurogenesis in Alzheimer's disease. J Psychosom Res. 2006; 61: 311-6.
120. Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006; 24: 1-14.