Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

The pathological mechanism by which Aβ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric Aβ (oAβ) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oAβ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oAβ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oAβ on FAT. Both oAβ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.

[1]  R. Llinás,et al.  Synaptic transmission block by presynaptic injection of oligomeric amyloid beta , 2009, Proceedings of the National Academy of Sciences.

[2]  A. Kozikowski,et al.  The amino terminus of tau inhibits kinesin‐dependent axonal transport: Implications for filament toxicity , 2009, Journal of neuroscience research.

[3]  K. Lapane,et al.  Dementia of the Alzheimer type. , 2008, Epidemiologic reviews.

[4]  Bin Wang,et al.  Conventional kinesin holoenzymes are composed of heavy and light chain homodimers. , 2008, Biochemistry.

[5]  Kim N. Green,et al.  Intracellular amyloid-β in Alzheimer's disease , 2007, Nature Reviews Neuroscience.

[6]  H. Saisu,et al.  Phosphorylated synaphin/complexin found in the brain exhibits enhanced SNARE complex binding. , 2007, Biochemical and biophysical research communications.

[7]  R. Llinás,et al.  1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C , 2007, Proceedings of the National Academy of Sciences.

[8]  W. Klein,et al.  Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease , 2007, The Journal of Neuroscience.

[9]  S. Moro,et al.  Tetrabromocinnamic Acid (TBCA) and Related Compounds Represent a New Class of Specific Protein Kinase CK2 Inhibitors , 2007, Chembiochem : a European journal of chemical biology.

[10]  Thomas H. Gillingwater,et al.  Synaptic Vulnerability in Neurodegenerative Disease , 2006, Journal of neuropathology and experimental neurology.

[11]  G. Pigino,et al.  JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport , 2006, Nature Neuroscience.

[12]  J. Busciglio,et al.  Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons , 2006, The Journal of Neuroscience.

[13]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[14]  S. Maeda,et al.  Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer's disease , 2006, Neuroscience Research.

[15]  Richard M. Page,et al.  Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease , 2005, Neuroscience.

[16]  M. Coleman.  Axon degeneration mechanisms: commonality amid diversity , 2005, Nature Reviews Neuroscience.

[17]  L. Pinna,et al.  2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2. , 2004, Biochemical and biophysical research communications.

[18]  G. Pigino,et al.  A novel CDK5‐dependent pathway for regulating GSK3 activity and kinesin‐driven motility in neurons , 2004, The EMBO journal.

[19]  C. Almeida,et al.  Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain , 2004, The Journal of Neuroscience.

[20]  Scott T. Brady,et al.  Neuropathogenic Forms of Huntingtin and Androgen Receptor Inhibit Fast Axonal Transport , 2003, Neuron.

[21]  Mark P Mattson,et al.  Alzheimer's Presenilin 1 Mutations Impair Kinesin-Based Axonal Transport , 2003, The Journal of Neuroscience.

[22]  Yasushi Hiraoka,et al.  Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport , 2003, Science.

[23]  G. Krafft,et al.  In Vitro Characterization of Conditions for Amyloid-β Peptide Oligomerization and Fibrillogenesis* , 2003, The Journal of Biological Chemistry.

[24]  L. Pinna,et al.  One‐thousand‐and‐one substrates of protein kinase CK2? , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  M. Pericak-Vance,et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). , 2002, American journal of human genetics.

[26]  P. Greengard,et al.  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. , 2002, The American journal of pathology.

[27]  W. Klein.  Aβ toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets , 2002, Neurochemistry International.

[28]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[29]  L. K. Baker,et al.  Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability* , 2002, The Journal of Biological Chemistry.

[30]  M. Donelan,et al.  Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis. , 2002, The Journal of biological chemistry.

[31]  Caine W. Wong,et al.  Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome , 2002, Neuron.

[32]  A. LeBlanc,et al.  Selective cytotoxicity of intracellular amyloid β peptide1–42 through p53 and Bax in cultured primary human neurons , 2002, The Journal of cell biology.

[33]  Nancy Ratner,et al.  Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin‐based motility , 2002, The EMBO journal.

[34]  S. Brady,et al.  Regulation of Kinesin: Implications for Neuronal Development , 2001, Developmental Neuroscience.

[35]  J. Troncoso,et al.  Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. , 2001, Archives of pathology & laboratory medicine.

[36]  J. Busciglio,et al.  Presenilin-1 Mutations Reduce Cytoskeletal Association, Deregulate Neurite Growth, and Potentiate Neuronal Dystrophy and Tau Phosphorylation , 2001, The Journal of Neuroscience.

[37]  R. Llinás,et al.  Nerve growth factor acutely reduces chemical transmission by means of postsynaptic TrkA-like receptors in squid giant synapse. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Brady,et al.  Immunochemical analysis of kinesin light chain function. , 1997, Molecular biology of the cell.

[40]  E. Braak,et al.  Distribution, Levels, and Activity of Glycogen Synthase Kinase‐3 in the Alzheimer Disease Brain , 1997, Journal of neuropathology and experimental neurology.

[41]  H. Wiśniewski,et al.  Amyloid β-protein stimulates casein kinase I and casein kinase II activities , 1993, Brain Research.

[42]  J. Trojanowski,et al.  Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[44]  E. Masliah,et al.  Casein kinase II alteration precedes tau accumulation in tangle formation. , 1992, The American journal of pathology.

[45]  D. Selkoe,et al.  Amyloid β-protein deposition in tissues other than brain in Alzheimer's disease , 1989, Nature.

[46]  E. Masliah,et al.  Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease , 1989, Neuroscience Letters.

[47]  G. Pigino,et al.  Approaches to kinesin-1 phosphorylation. , 2007, Methods in molecular biology.

[48]  W. Klein,et al.  Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  Michela Gallagher,et al.  A specific amyloid-beta protein assembly in the brain impairs memory. , 2006, Nature.

[50]  D. Gubb,et al.  Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease. , 2005, Neuroscience.

[51]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[52]  Li-Huei Tsai,et al.  Cdk5: one of the links between senile plaques and neurofibrillary tangles? , 2003, Journal of Alzheimer's disease : JAD.

[53]  J. Busciglio,et al.  Fast axonal transport misregulation and Alzheimer’s Disease , 2002, NeuroMolecular Medicine.

[54]  H. Braak,et al.  Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. , 2001, Journal of Alzheimer's disease : JAD.

[55]  P. Greengard,et al.  Intraneuronal Abeta42 accumulation in human brain. , 2000, The American journal of pathology.

[56]  P. Greengard,et al.  Intraneuronal Aβ42 Accumulation in Human Brain , 2000 .

[57]  C. Bieberich,et al.  The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice , 1995, Nature Genetics.

[58]  S. Brady,et al.  Assay of vesicle motility in squid axoplasm. , 1993, Methods in cell biology.

[59]  H. Wiśniewski,et al.  Amyloid beta-protein stimulates casein kinase I and casein kinase II activities. , 1993, Brain research.

[60]  R. Lasek,et al.  Video microscopy of fast axonal transport in extruded axoplasm: a new model for study of molecular mechanisms. , 1985, Cell motility.