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• Intracellular amyloid-beta in Alzheimer's disease.
• Citation:
  LaFerla F, Green K, Oddo S
  

  Intracellular amyloid-beta in Alzheimer's disease.

  Nature reviews. Neuroscience. 2007 Jul;8(7):499-509
  [PubMed] [Alzforum]
• Supporting:
  • Neuritic plaques are relevant to AD.

    SHOW Details   Supporting(11)   Consistent(1) 

    Description: Neuritic plaques have been considered as a probable cause of neuronal degeneration and death in AD long before the discovery that plaques contain Aβ. Since then, evidence has accumulated indicating that Aβ may be responsible – at least in part – for the pathology and symptoms of AD. It appeared that the oligomerization state of the peptide is highly relevant to Aβ toxicity. Aβ is generated from APP likely as monomer, while mature plaques contain Aβ fibrils, which form as a result of peptide aggregation. Between monomers and fibrils, there are many oligomeric forms – from dimers and trimers to Aβ-derived diffusible ligands (ADDLs), annular assemblies, and protofibrils (the latter forms being mainly the result of in vitro polymerization). Recent work has shown that it is the presence of the soluble Aβ oligomers (dimers, trimers, or higher oligomers, such as Aβ*56) rather than the fibrillar Aβ and the brain plaque load which correlates with the learning and memory deficits, in mouse models of AD. If the fibrillar Aβ present in mature plaques is less toxic than the oligomers, then are the neuritic plaques less relevant to AD pathology than the soluble Aβ oligomers? Not at all! Recent studies suggest that the plaques might function as reservoirs of the highly pathogenic, smaller Aβ oligomers, from which they can be released.
    Experimental Approach: Mechanism - biochemistry and structural biology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I, Brett F, Farrell M, Rowan M, Lemere C, Regan C, Walsh D, Sabatini B, Selkoe D
      Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      Nature medicine. 2008 Aug;14(8):837-42
    • LaFerla F, Green K, Oddo S
      Intracellular amyloid-beta in Alzheimer's disease.
      Nature reviews. Neuroscience. 2007 Jul;8(7):499-509
    • Glenner G, Wong C
      Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
      Biochemical and biophysical research communications. 1984 May 16;120(3):885-90
    • Cleary J, Walsh D, Hofmeister J, Shankar G, Kuskowski M, Selkoe D, Ashe K
      Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
      Nature neuroscience. 2005 Jan;8(1):79-84
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Martins I, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F
      Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
      The EMBO journal. 2008 Jan 9;27(1):224-33
    • Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W
      Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
      Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53
    • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R
      APP processing and synaptic function.
      Neuron. 2003 Mar 27;37(6):925-37
    • Haass C, Selkoe D
      Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
      Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12
    • Masters C, Simms G, Weinman N, Multhaup G, McDonald B, Beyreuther K
      Amyloid plaque core protein in Alzheimer disease and Down syndrome.
      Proceedings of the National Academy of Sciences of the United States of America. 1985 Jun;82(12):4245-9

    Consistent statements
    

    • The invariant accumulation of insoluble amyloid plaques in AD may signify that they serve as relatively inert reservoirs of small bioactive oligomers, and they may disassemble more readily in the presence of lipids. Shankar G  Li S  Mehta T  Garcia-Munoz A  Shepardson N  Smith I  Brett F  Farrell M  Rowan M  Lemere C  Regan C  Walsh D  Sabatini B  Selkoe D 
  • CAD cells are a useful model system for studying cellular processes related Alzheimer’s disease pathology, including post-translational processing of APP and intraneuronal oligomerization of Aβ.

    SHOW Details   Supporting(8) 

    Description: CAD cells have been used to study the proteolytic processing by secretases, and the phosphorylation of APP, in conditions relevant to Alzheimer’s disease. CAD cells are prone to intracellular oligomerization and neuritic accumulation of Aβ, and have been used to study these processes in relation to Alzheimer’s disease. CAD cells also secrete Aβ and soluble, N-terminal fragments (sAPPs) into the medium. Since the issue of the neuronal toxicity of secreted versus intracellular, oligomeric Aβ is one of the hottest topics in AD research, CAD cells may offer a novel system to test these two hypotheses.
    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Mechanism - molecular and cell
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Muresan Z, Muresan V
      Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
      Molecular and cellular biology. 2006 Jul;26(13):4982-97
    • Lee M, Kao S, Lemere C, Xia W, Tseng H, Zhou Y, Neve R, Ahlijanian M, Tsai L
      APP processing is regulated by cytoplasmic phosphorylation.
      The Journal of cell biology. 2003 Oct 13;163(1):83-95
    • Muresan Z, Muresan V
      Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology.
      Neuro-degenerative diseases. 2008;5(3-4):250-3
    • Muresan Z, Muresan V
      A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment.
      Human molecular genetics. 2004 Mar 1;13(5):475-88
    • LaFerla F, Green K, Oddo S
      Intracellular amyloid-beta in Alzheimer's disease.
      Nature reviews. Neuroscience. 2007 Jul;8(7):499-509
    • Muresan Z, Muresan V
      c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Apr 13;25(15):3741-51
    • Haass C, Selkoe D
      Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
      Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12
    • Muresan Z, Muresan V
      The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
      Molecular biology of the cell. 2007 Oct;18(10):3835-44
• Created On: Tue, Dec 02 10:50:47 EST 2008
• Last Modified On: Tue Dec 02 10:50:47 EST 2008