Home LiteratureArticle Details
PMID: 16782885 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.

Molecular and cellular biology ·Vol. 26 ·No. 13 ·2006-07-00 ·Pages 4982-97

Muresan Z, Muresan V

Abstract

Our goal is to understand the pathogenesis of amyloid-beta (Abeta) deposition in the Alzheimer's disease (AD) brain. We established a cell culture system where central nervous system-derived neuronal cells (CAD cells) produce and accumulate within their processes large amounts of Abeta peptide, similar to what is believed to occur in brain neurons, in the initial phases of AD. Using this system, we show that accumulation of Abeta begins within neurites, prior to any detectable signs of neurodegeneration or abnormal vesicular transport. Neuritic accumulation of Abeta is restricted to a small population of neighboring cells that express normal levels of amyloid-beta precursor protein (APP) but show redistribution of BACE1 to the processes, where it colocalizes with Abeta and markers of late endosomes. Consistently, cells that accumulate Abeta appear in isolated islets, suggesting their clonal origin from a few cells that show a propensity to accumulate Abeta. These results suggest that Abeta accumulation is initiated in a small number of neurons by intracellular determinants that alter APP metabolism and lead to Abeta deposition and neurodegeneration. CAD cells appear to recapitulate the biochemical processes leading to Abeta deposition, thus providing an experimental in vitro system for studying the molecular pathobiology of AD.

MeSH Terms
Alzheimer Disease/metabolism,pathology Amyloid Precursor Protein Secretases Amyloid beta-Peptides/analysis,metabolism Animals Apoptosis Aspartic Acid Endopeptidases Cells, Cultured Central Nervous System/chemistry,metabolism,pathology Endopeptidases/analysis Mice Necrosis/pathology Neurites/chemistry,metabolism,pathology Neurons/chemistry,metabolism,pathology
Chemicals
Amyloid beta-Peptides Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases Bace1 protein, mouse
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Muresan Zoia
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4970, USA.
Muresan Virgil
References (58)
58 references, click to expand
  1. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
    Science. 1999 Oct 22;286(5440):735-41 PMID: 10531052
  2. gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?
    Nat Rev Neurosci. 2002 Apr;3(4):281-90 PMID: 11967558
  3. Purification and cloning of amyloid precursor protein beta-secretase from human brain.
    Nature. 1999 Dec 2;402(6761):537-40 PMID: 10591214
  4. Identification of a novel aspartic protease (Asp 2) as beta-secretase.
    Mol Cell Neurosci. 1999 Dec;14(6):419-27 PMID: 10656250
  5. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein.
    Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60 PMID: 10677483
  6. Proteolytic processing and cell biological functions of the amyloid precursor protein.
    J Cell Sci. 2000 Jun;113 ( Pt 11):1857-70 PMID: 10806097
  7. Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells.
    Hum Mol Genet. 2000 May 22;9(9):1403-13 PMID: 10814722
  8. Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5.
    J Neurochem. 2000 Sep;75(3):1085-91 PMID: 10936190
  9. Disease-specific patterns of locus coeruleus cell loss.
    Ann Neurol. 1992 Nov;32(5):667-76 PMID: 1449247
  10. Catecholaminergic cell lines from the brain and adrenal glands of tyrosine hydroxylase-SV40 T antigen transgenic mice.
    J Neurosci. 1993 Mar;13(3):1280-91 PMID: 7680068
  11. Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons.
    J Cell Biol. 1995 Apr;129(2):431-42 PMID: 7721945
  12. Rab 7: an important regulator of late endocytic membrane traffic.
    J Cell Biol. 1995 Dec;131(6 Pt 1):1435-52 PMID: 8522602
  13. Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation.
    J Neurosci. 1997 Feb 15;17(4):1217-25 PMID: 9006967
  14. Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.
    Nat Med. 1997 Sep;3(9):1021-3 PMID: 9288730
  15. Frequency of stages of Alzheimer-related lesions in different age categories.
    Neurobiol Aging. 1997 Jul-Aug;18(4):351-7 PMID: 9330961
  16. Thyroglobulin transport along the secretory pathway. Investigation of the role of molecular chaperone, GRP94, in protein export from the endoplasmic reticulum.
    J Biol Chem. 1997 Oct 17;272(42):26095-102 PMID: 9334173
  17. KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles.
    Mol Biol Cell. 1998 Mar;9(3):637-52 PMID: 9487132
  18. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain.
    J Neurosci. 1998 Apr 15;18(8):2801-7 PMID: 9525997
  19. Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture.
    J Cell Biol. 1998 May 18;141(4):1031-9 PMID: 9585420
  20. Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation.
    J Neurosci. 1999 Jun 1;19(11):4421-7 PMID: 10341243
  21. Translating cell biology into therapeutic advances in Alzheimer's disease.
    Nature. 1999 Jun 24;399(6738 Suppl):A23-31 PMID: 10392577
  22. Intracellular APP processing and A beta production in Alzheimer disease.
    J Neuropathol Exp Neurol. 1999 Aug;58(8):787-94 PMID: 10446803
  23. Altered amyloid-beta metabolism and deposition in genomic-based beta-secretase transgenic mice.
    J Biol Chem. 2004 Dec 10;279(50):52535-42 PMID: 15452128
  24. BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo.
    J Cell Biol. 2005 Jan 17;168(2):291-302 PMID: 15642747
  25. Axonal transport defects: a common theme in neurodegenerative diseases.
    Acta Neuropathol. 2005 Jan;109(1):5-13 PMID: 15645263
  26. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease.
    Science. 2005 Feb 25;307(5713):1282-8 PMID: 15731448
  27. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.
    Neuron. 2005 Mar 3;45(5):675-88 PMID: 15748844
  28. c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
    J Neurosci. 2005 Apr 13;25(15):3741-51 PMID: 15829626
  29. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition.
    Nature. 2005 Jun 16;435(7044):903-10 PMID: 15959507
  30. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance.
    Annu Rev Neurosci. 2005;28:403-50 PMID: 16022602
  31. Metabolic activity: a novel indicator of neuronal survival in the murine dopaminergic cell line CAD.
    J Mol Neurosci. 2005;27(1):65-77 PMID: 16055947
  32. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease.
    Neurobiol Aging. 2005 Oct;26(9):1235-44 PMID: 16023263
  33. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.
    J Cell Biol. 2005 Oct 10;171(1):87-98 PMID: 16203860
  34. The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.
    J Comp Neurol. 2005 Nov 28;492(4):469-76 PMID: 16228992
  35. Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
    J Cell Biol. 2005 Nov 21;171(4):615-25 PMID: 16301330
  36. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease.
    Ann Neurol. 2002 Jun;51(6):783-6 PMID: 12112088
  37. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
    Science. 2002 Jul 19;297(5580):353-6 PMID: 12130773
  38. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
    Arch Neurol. 2002 Sep;59(9):1381-9 PMID: 12223024
  39. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
    Am J Pathol. 2002 Nov;161(5):1869-79 PMID: 12414533
  40. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease.
    Nat Med. 2003 Jan;9(1):3-4 PMID: 12514700
  41. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.
    Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8 PMID: 12566568
  42. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
    Science. 2003 Apr 18;300(5618):486-9 PMID: 12702875
  43. Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes.
    J Cell Sci. 2003 Aug 15;116(Pt 16):3339-46 PMID: 12829747
  44. APP processing is regulated by cytoplasmic phosphorylation.
    J Cell Biol. 2003 Oct 13;163(1):83-95 PMID: 14557249
  45. A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment.
    Hum Mol Genet. 2004 Mar 1;13(5):475-88 PMID: 14722157
  46. Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain.
    J Neurosci. 2004 Apr 7;24(14):3592-9 PMID: 15071107
  47. The early onset dystonia protein torsinA interacts with kinesin light chain 1.
    J Biol Chem. 2004 May 7;279(19):19882-92 PMID: 14970196
  48. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2687-97 PMID: 15138286
  49. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia.
    Neurology. 1982 Feb;32(2):164-8 PMID: 7198741
  50. Efferent projections of nucleus locus coeruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction.
    Neuroscience. 1986 Jun;18(2):291-306 PMID: 3736860
  51. The neuropathology of aminergic nuclei in Alzheimer's disease.
    Ann Neurol. 1988 Aug;24(2):233-42 PMID: 3178178
  52. Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules.
    J Cell Biol. 2001 Mar 5;152(5):959-70 PMID: 11238452
  53. Alzheimer's disease: genes, proteins, and therapy.
    Physiol Rev. 2001 Apr;81(2):741-66 PMID: 11274343
  54. One axon, many kinesins: What's the logic?
    J Neurocytol. 2000 Nov-Dec;29(11-12):799-818 PMID: 11466472
  55. The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.
    J Biol Chem. 2001 Sep 28;276(39):36788-96 PMID: 11466313
  56. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease.
    J Mol Neurosci. 2001 Oct;17(2):137-45 PMID: 11816787
  57. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP.
    Nature. 2001 Dec 6;414(6864):643-8 PMID: 11740561
  58. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
    Nature. 1999 Dec 2;402(6761):533-7 PMID: 10591213
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00371-06
Published
2006-07-00
Pages
4982-97
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1489158
Subset
IM
Grants
NIGMS NIH HHS · R01 GM068596 · United States
NIGMS NIH HHS · 5R01GM068596-02 · United States
External Links
PubMed source DOI: 10.1128/MCB.00371-06 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2