The Extensive Nitration of Neurofilament Light Chain in the Hippocampus Is Associated with the Cognitive Impairment Induced by Amyloid β in Mice

Tyrosine nitration of proteins at an extensive level is widely associated with the cognitive pathology induced by amyloid β peptide (Aβ). However, the precise identity and explicit consequences of protein nitration have scarcely been addressed. In this study, we examined the detectable nitration of proteins in the hippocampus of mice with cognitive impairment (day 5) induced by the i.c.v. injection of Aβ25–35 (day 0). The intensity of the nitration of proteins was inversely associated with the level of recognition memory in mice. The detectable tyrosine nitrations were revealed in proteins with a single size of approximately 70 kDa. The specific nitrated proteins at this size were identified using the liquid chromatography/mass spectrometry/mass spectrometry analysis and immunodetection methods. Intense nitration of the neurofilament light chain (NFL) was observed. The increased nitration of NFL was associated with its serine hyperphosphorylation and weak interaction with the nuclear distribution element-like, a protein essential for the stable assembly of neurofilaments. No changes in cell numbers in the hippocampus were found (day 5) in mice that received Aβ25–35 injections. These findings suggested that extensive nitration of NFL is associated with the Aβ-induced impairment of recognition memory in mice.

[1]  T. Nabeshima,et al.  Restraining tumor necrosis factor-alpha by thalidomide prevents the Amyloid beta-induced impairment of recognition memory in mice , 2008, Behavioural Brain Research.

[2]  D. Holtzman,et al.  Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease , 2008, Nature.

[3]  T. Nabeshima,et al.  A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Aβ25–35 , 2007, Behavioural Brain Research.

[4]  R. Berry,et al.  Nitration in neurodegeneration: deciphering the "Hows" "nYs". , 2007, Biochemistry.

[5]  Richard D. Smith,et al.  Endogenously nitrated proteins in mouse brain: links to neurodegenerative disease. , 2006, Biochemistry.

[6]  D. Butterfield,et al.  Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach , 2006, Neurobiology of Disease.

[7]  E. Masliah,et al.  Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease , 2005, Science.

[8]  Dominic M. Walsh,et al.  Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease , 2004, Neuron.

[9]  R. Quirion,et al.  Natural antioxidants and neurodegenerative diseases. , 2004, Frontiers in bioscience : a journal and virtual library.

[10]  J. Andersen,et al.  Oxidative stress in neurodegeneration: cause or consequence? , 2004, Nature Reviews Neuroscience.

[11]  Sang Ki Park,et al.  A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons , 2004, Nature Cell Biology.

[12]  K. Komatsu,et al.  Repair of amyloid β(25–35)-induced memory impairment and synaptic loss by a Kampo formula, Zokumei-to , 2003, Brain Research.

[13]  O. Ottersen,et al.  Immunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo , 2003, Neuroscience.

[14]  H. Ischiropoulos,et al.  Biological selectivity and functional aspects of protein tyrosine nitration. , 2003, Biochemical and biophysical research communications.

[15]  Visith Thongboonkerd,et al.  Proteomic identification of nitrated proteins in Alzheimer's disease brain , 2003, Journal of neurochemistry.

[16]  T. Nabeshima,et al.  Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction , 2003, Molecular Psychiatry.

[17]  Xiongwei Zhu,et al.  Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases? , 2002, Free radical biology & medicine.

[18]  T. Kubo,et al.  In vivo conversion of racemized β‐amyloid ([D‐Ser26]Aβ1–40) to truncated and toxic fragments ([D‐Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patients , 2002 .

[19]  G. Cole,et al.  The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse , 2001, The Journal of Neuroscience.

[20]  D. Butterfield,et al.  Peroxynitrite‐Induced Alterations in Synaptosomal Membrane Proteins , 1999, Journal of neurochemistry.

[21]  T. Kameyama,et al.  Protective effects of idebenone and α‐tocopherol on β‐amyloid‐(1–42)‐induced learning and memory deficits in rats: implication of oxidative stress in β‐amyloid‐induced neurotoxicity in vivo , 1999 .

[22]  M. Strong,et al.  Nitration of the low molecular weight neurofilament is equivalent in sporadic amyotrophic lateral sclerosis and control cervical spinal cord. , 1998, Biochemical and biophysical research communications.

[23]  T. Hasegawa,et al.  Continuous infusion of beta-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. , 1998, Japanese journal of pharmacology.

[24]  S. Barnes,et al.  Superoxide Dismutase Catalyzes Nitration of Tyrosines by Peroxynitrite in the Rod and Head Domains of Neurofilament‐L , 1997, Journal of neurochemistry.

[25]  J. Julien,et al.  Delayed Maturation of Regenerating Myelinated Axons in Mice Lacking Neurofilaments , 1997, Experimental Neurology.

[26]  P Woodbury,et al.  A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. , 1997, The New England journal of medicine.

[27]  Joseph S. Beckman,et al.  Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease , 1997, The Journal of Neuroscience.

[28]  Christopher C. J. Miller,et al.  Assembly Properties of Neurofilament Light Chain Ser55 Mutants in Transfected Mammalian Cells , 1996, Journal of neurochemistry.

[29]  A. Privat,et al.  Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction , 1996, Brain Research.

[30]  C. Cotman,et al.  Structure‐Activity Analyses of β‐Amyloid Peptides: Contributions of the β25–35 Region to Aggregation and Neurotoxicity , 1995 .

[31]  P. Keyser,et al.  Interval between the synthesis and assembly of cytoskeletal proteins in cultured neurons , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  A. Scaloni,et al.  Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. , 2005, Mass spectrometry reviews.

[33]  E. Holzbaur.  Tangled NUDELs? , 2004, Nature Cell Biology.

[34]  T. Kubo,et al.  In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1-40) to truncated and toxic fragments ([D-Ser 26]A beta 25-35/40) and fragment presence in the brains of Alzheimer's patients. , 2002, Journal of neuroscience research.

[35]  Y. Aoyama,et al.  Pemphigus vulgaris-IgG causes a rapid depletion of desmoglein 3 (Dsg3) from the Triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous carcinoma cell line, DJM-1 cells. , 1999, The Journal of investigative dermatology.

[36]  T. Kameyama,et al.  Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. , 1999, The European journal of neuroscience.

[37]  T. Shea,et al.  Neurofilament subunits can undergo axonal transport without incorporation into Triton-insoluble structures. , 1998, Cell motility and the cytoskeleton.

[38]  R. Nixon,et al.  Dynamics of neuronal intermediate filaments: a developmental perspective. , 1992, Cell motility and the cytoskeleton.

[39]  T. Kameyama,et al.  Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice. , 1991, The Journal of pharmacology and experimental therapeutics.

[40]  N. Hirokawa,et al.  Effects of phosphorylation of the neurofilament L protein on filamentous structures. , 1990, Cell regulation.

[41]  J. Silberberg.  Estimating the benefits of cholesterol lowering: are risk factors for coronary heart disease multiplicative? , 1990, Journal of clinical epidemiology.