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• Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
• Citation:
  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
  [PubMed] [Alzforum]
• Supporting:
  • Brainstem neurons, as initiators of senile plaques, have relevance for AD therapeutics and drug discovery.

    SHOW Details   Supporting(6) 

    Description: By pointing to a specific group of neurons (from the brainstem) as initiators of senile plaques, our hypothesis may offer a novel perspective on AD pathogenesis. The neuronal cell system that is used in our studies is ideally suited for screening of compounds that may be good candidates for prevention of formation of senile plaques, and could potentially be used to treat brainstem neurons in early phases of AD.
    Experimental Approach: Target validation,   Mechanism - biochemistry and structural biology,   Pathophysiology
    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
    • 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
    • Muresan Z, Muresan V
      Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
      The Journal of cell biology. 2005 Nov 21;171(4):615-25
    • 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
    • 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
      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
  • Neuritic accumulation of Aβ is restricted to a small population of neighboring cells, in CAD cell cultures.

    SHOW Details   Supporting(1) 

    Description: An interesting observation was that CAD cells that accumulate Aβ in their processes represent a small fraction of the total cells, and appear in islet-like clusters, segregated from the dominant, conventional cells. Since CAD cells divide when cultured in the presence of serum, it seems likely that the cells contained within each separate cluster originated from one, or a few cells prone to increased generation of Aβ. Alternatively, extrinsic factors that may randomly be generated in parts of the cell culture dish could trigger changes in the metabolism of a few cells, leading to abnormal APP processing and neuritic accumulation of Aβ. Non-homogeneities in the culture dish may arise in different ways, including local variation in cell density.
    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Initial condition
    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
  • CAD cell are a useful model for studying a potential role of brainstem neurons in the initiation of neuritic plaques in Alzheimer’s disease.

    SHOW Details   Supporting(2)   Consistent(2) 

    Experimental Approach: Animal models,   Pathophysiology,  
    Pathogenic Narrative Tags: Perturbation
    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
    • 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

    Consistent statements
    

    • Cultured neuronal cells originating from the brainstem - but not neurons derived from the cerebral cortex or hippocampus - accumulate oligomerized Aβ at the terminals of their processes. Muresan Z  Muresan V 
    • Brainstem neurons are initiators of neuritic plaques. Muresan Z  Muresan V 
  • 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
  • The composition of the Aβ accumulations is complex, and includes many species of Aβ oligomers.

    SHOW Details   Supporting(2)   Consistent(4) 

    Description: The use of the monoclonal antibody 6E10 (raised against human Aβ) to detect the neuritic Aβ accumulations in the mouse cell line, CAD may be of some concern, since the epitope recognized by this antibody lies within a region that is not fully conserved between humans and mice. However, the 6E10 antibody cross-reacts with mouse Aβ, when it is present at high concentration, both in immunocytochemistry and Western blots. Moreover, characterization of the 6E10-immunoreactive material in CAD cells with a series of other antibodies to Aβ, and antibodies to different regions of APP, confirmed that it contained bona fide Aβ and not the full length APP, sAPPs, or CTFs. Using carboxy-terminal-end antibodies to Aβ species, we showed that the neuritically accumulated material contains both Aβ40 and Aβ42. Cross-reactivity of the accumulations with an anti-oligomer antibody (A11) indicated that they include high-number oligomeric species. However, the accumulations also include low-number Aβ oligomers detectable in Western blots as dimers and trimers.
    Experimental Approach: Mechanism - biochemistry and structural biology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Kayed R, Head E, Thompson J, McIntire T, Milton S, Cotman C, Glabe C
      Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
      Science (New York, N.Y.). 2003 Apr 18;300(5618):486-9
    • 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

    Consistent statements
    

    • Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R 
    • A form of oligomeric soluble Aβ may be the neurotoxic species, and ApoE may facilitate the formation of these species. Holtzman D 
    • Prefibrillar Aβ assemblies may be neurotoxic in vivo. Hardy J  Selkoe D 
    • AD diffusible ligands (ADDLs) or protofibrils cause injury to cultured neurons. Hardy J  Selkoe D 
  • CAD cells that accumulate Aβ show redistribution of β-secretase (BACE1) to the processes, where it co-localizes with Aβ.

    SHOW Details   Supporting(7)   Consistent(1)     Genes/Proteins: (1)

    Description: CAD cells that contain Aβ accumulations within neurites also contain BACE1, the major β-secretase, at the same location, coincident with Aβ. The extent of BACE1 accumulation within the neuronal processes of these cells is abnormal, since this enzyme is normally localized to Golgi compartments and early endosomes in the cell body. This result suggests that, in vivo, mislocalization of BACE1 may cause the production and accumulation of Aβ within processes and synaptic regions. This result is in line with a recent report that proposes that BACE1 localization – in addition to its expression level - determines the amount of generated Aβ and its accumulation in plaques.
    Experimental Approach: Mechanism - biochemistry and structural biology,   Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Fukumoto H, Cheung B, Hyman B, Irizarry M
      Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
      Archives of neurology. 2002 Sep;59(9):1381-9
    • Yan R, Han P, Miao H, Greengard P, Xu H
      The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.
      The Journal of biological chemistry. 2001 Sep 28;276(39):36788-96
    • Holsinger R, McLean C, Beyreuther K, Masters C, Evin G
      Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease.
      Annals of neurology. 2002 Jun;51(6):783-6
    • Yang L, Lindholm K, Yan R, Citron M, Xia W, Yang X, Beach T, Sue L, Wong P, Price D, Li R, Shen Y
      Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease.
      Nature medicine. 2003 Jan;9(1):3-4
    • 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
    • Kinoshita A, Fukumoto H, Shah T, Whelan C, Irizarry M, Hyman B
      Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes.
      Journal of cell science. 2003 Aug 15;116(Pt 16):3339-46
    • Lee E, Zhang B, Liu K, Greenbaum E, Doms R, Trojanowski J, Lee V
      BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo.
      The Journal of cell biology. 2005 Jan 17;168(2):291-302

    Consistent statements
    

    • Aβ induces local neurite degeneration referred to as neuritic apoptosis or synaptotosis which displays the morphological and biochemical characteristics of apoptosis. Thus neurite degeneration may use mechanisms common to apoptotsis. Cotman C 

    Genes/Proteins
    

    • Protein: Beta-secretase 1 [Mus musculus]
  • Accumulation of Aβ begins within neurites, prior to any major signs of neurodegeneration or cell death, although the terminals that contain accumulations appear dystrophic.

    SHOW Details   Supporting(1)   Consistent(4) 

    Description: Morphologically, CAD cells containing Aβ accumulations appear normal; they are not undergoing degeneration or cell death. Indeed, they do not reveal any detachment of their processes from the cell bodies (typical for a Wallerian-like degenerative process), nor do they show signs of plasmalemmal disintegration (typical for necrosis) or nuclear fragmentation (typical for apoptosis). However, their terminals appear somewhat distended.
    Experimental Approach: Mechanism - biochemistry and structural biology
    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

    Consistent statements
    

    • Imaging of neurite dystrophy and new plaque formation over time demonstrated that in the days after plaque formation, progressive neuritic alterations were evident: from a smooth bend around the new plaque to very tortuous changes identical in appearance to dystrophic neurites seen in Alzheimer’s disease Meyer-Luehmann M  Spires-Jones T  Prada C  Garcia-Alloza M  de Calignon A  Rozkalne A  Koenigsknecht-Talboo J  Holtzman D  Bacskai B  Hyman B 
    • In parallel with characteristic AD pathology, Aβ induces the formation of dystrophic neurites in cultured neurons. Cotman C  Su J 
    • Aβ induces local neurite degeneration referred to as neuritic apoptosis or synaptotosis which displays the morphological and biochemical characteristics of apoptosis. Thus neurite degeneration may use mechanisms common to apoptotsis. Cotman C 
    • Cell death in human AD brains is not well correlated with Alzheimer Disease progression. Dziewczapolski G  Glogowski C  Masliah E  Heinemann S 
  • CAD cells are a useful model for studies of APP cell biology and Alzheimers disease pathology, including Aβ accumulation within neurites.

    SHOW Details   Supporting(7) 

    Description: This hypothesis describes the use of CAD cells as a model system to study the cell biology of APP, including its metabolism, intracellular transport, function, and implication in neuronal degeneration. CAD cells express the neuronal form of APP (APP695), a fraction of which is transported within neurites at velocities similar to those reported for cultured hippocampal neurons. Like in neurons, in CAD cells, APP is processed by secretase activities to generate sAPPs, Aβ, and CTFs - including the AICD (part of which is translocated into the nucleus). Both the full-length APP and the CTFs become phosphorylated – via multiple signaling pathways - at a critical threonine residue in the cytoplasmic domain (Thr668 in APP695). Aβ is produced intracellularly in CAD cells, and forms low- and high-number oligomers that occasionally accumulate at neurite terminals. Thus, an essential feature of the neuronal pathology thought to occur in Alzheimer’s disease can be reproduced – and studied - in CAD cells.
    Contained Discourse: 10 Elements
    Experimental Approach:
    Pathogenic Narrative Tags:
    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
    • 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
    • Muresan Z, Muresan V
      Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
      The Journal of cell biology. 2005 Nov 21;171(4):615-25
    • 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
    • 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
    • Muresan V, Varvel N, Lamb B, Muresan Z
      The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009 Mar 18;29(11):3565-78
• Created On: Tue, Nov 11 10:51:16 EST 2008
• Last Modified On: Tue Nov 11 10:51:16 EST 2008